Cells

15 pages, 1844 KB

Open AccessEditor’s ChoiceReview

The Memory T Cell “Communication Web” in Context with Gastrointestinal Disorders—How Memory T Cells Affect Their Surroundings and How They Are Influenced by It

by Annkathrin Knauss, Michael Gabel, Markus F. Neurath and Benno Weigmann

Cells 2022, 11(18), 2780; https://doi.org/10.3390/cells11182780 - 6 Sep 2022

Cited by 4 | Viewed by 4533

Abstract

Gut-related diseases like ulcerative colitis, Crohn’s disease, or colorectal cancer affect millions of people worldwide. It is an ongoing process finding causes leading to the development and manifestation of those disorders. This is highly relevant since understanding molecular processes and signalling pathways offers [...] Read more.

Gut-related diseases like ulcerative colitis, Crohn’s disease, or colorectal cancer affect millions of people worldwide. It is an ongoing process finding causes leading to the development and manifestation of those disorders. This is highly relevant since understanding molecular processes and signalling pathways offers new opportunities in finding novel ways to interfere with and apply new pharmaceuticals. Memory T cells (mT cells) and their pro-inflammatory properties have been proven to play an important role in gastrointestinal diseases and are therefore increasingly spotlighted. This review focuses on mT cells and their subsets in the context of disease pathogenesis and maintenance. It illustrates the network of regulatory proteins and metabolites connecting mT cells with other cell types and tissue compartments. Furthermore, the crosstalk with various microbes will be a subject of discussion. Characterizing mT cell interactions will help to further elucidate the sophisticated molecular and cellular networking system in the intestine and may present new ideas for future research approaches to control gut-related diseases. Full article

(This article belongs to the Special Issue ColoNet: Profiling Molecular and Cellular Networks in the Gastrointestinal Tract)

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17 pages, 1724 KB

Open AccessEditor’s ChoiceReview

Role of Microglia and Astrocytes in Alzheimer’s Disease: From Neuroinflammation to Ca²⁺ Homeostasis Dysregulation

by Giulia Di Benedetto, Chiara Burgaletto, Carlo Maria Bellanca, Antonio Munafò, Renato Bernardini and Giuseppina Cantarella

Cells 2022, 11(17), 2728; https://doi.org/10.3390/cells11172728 - 1 Sep 2022

Cited by 104 | Viewed by 12547

Abstract

Alzheimer’s disease (AD) is the most common form of dementia worldwide, with a complex, poorly understood pathogenesis. Cerebral atrophy, amyloid-β (Aβ) plaques, and neurofibrillary tangles represent the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as a prominent feature [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia worldwide, with a complex, poorly understood pathogenesis. Cerebral atrophy, amyloid-β (Aβ) plaques, and neurofibrillary tangles represent the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as a prominent feature of the AD brain and substantial evidence suggests that the inflammatory response modulates disease progression. Additionally, dysregulation of calcium (Ca²⁺) homeostasis represents another early factor involved in the AD pathogenesis, as intracellular Ca²⁺ concentration is essential to ensure proper cellular and neuronal functions. Although growing evidence supports the involvement of Ca²⁺ in the mechanisms of neurodegeneration-related inflammatory processes, scant data are available on its contribution in microglia and astrocytes functioning, both in health and throughout the AD continuum. Nevertheless, AD-related aberrant Ca²⁺ signalling in astrocytes and microglia is crucially involved in the mechanisms underpinning neuroinflammatory processes that, in turn, impact neuronal Ca²⁺ homeostasis and brain function. In this light, we attempted to provide an overview of the current understanding of the interactions between the glia cells-mediated inflammatory responses and the molecular mechanisms involved in Ca²⁺ homeostasis dysregulation in AD. Full article

(This article belongs to the Special Issue Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases)

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20 pages, 1610 KB

Open AccessEditor’s ChoiceReview

Postnatal and Adult Neurogenesis in Mammals, Including Marsupials

by Katarzyna Bartkowska, Beata Tepper, Krzysztof Turlejski and Ruzanna Djavadian

Cells 2022, 11(17), 2735; https://doi.org/10.3390/cells11172735 - 1 Sep 2022

Cited by 20 | Viewed by 5715

Abstract

In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a number of brain structures develop after birth. The exception is the generation of granule cells in the dentate gyrus, olfactory bulb, and [...] Read more.

In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a number of brain structures develop after birth. The exception is the generation of granule cells in the dentate gyrus, olfactory bulb, and cerebellum of eutherian species. The formation of these structures starts during embryogenesis and continues postnatally. In both eutherians and marsupials, neurogenesis continues in the subventricular zone of the lateral ventricle (SVZ) and the dentate gyrus of the hippocampal formation throughout life. The majority of proliferated cells from the SVZ migrate to the olfactory bulb, whereas, in the dentate gyrus, cells reside within this structure after division and differentiation into neurons. A key aim of this review is to evaluate advances in understanding developmental neurogenesis that occurs postnatally in both marsupials and eutherians, with a particular emphasis on the generation of granule cells during the formation of the olfactory bulb, dentate gyrus, and cerebellum. We debate the significance of immature neurons in the piriform cortex of young mammals. We also synthesize the knowledge of adult neurogenesis in the olfactory bulb and the dentate gyrus of marsupials by considering whether adult-born neurons are essential for the functioning of a given area. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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16 pages, 1852 KB

Open AccessEditor’s ChoiceArticle

BC-miR: Monitoring Breast Cancer-Related miRNA Profile in Blood Sera—A Prosperous Approach for Tumor Detection

by Barbara N. Borsos, Zoltán G. Páhi, Zsuzsanna Ujfaludi, Farkas Sükösd, Alíz Nikolényi, Sarolta Bankó, Gabriella Pankotai-Bodó, Orsolya Oláh-Németh and Tibor Pankotai

Cells 2022, 11(17), 2721; https://doi.org/10.3390/cells11172721 - 31 Aug 2022

Cited by 15 | Viewed by 3381

Abstract

Breast cancer is the most frequent cancer with a high fatality rate amongst women worldwide. Diagnosing at an early stage is challenging, and due to the limitations of the currently used techniques, including mammography and imaging diagnostics, it still remains unascertained. Serum biomarkers [...] Read more.

Breast cancer is the most frequent cancer with a high fatality rate amongst women worldwide. Diagnosing at an early stage is challenging, and due to the limitations of the currently used techniques, including mammography and imaging diagnostics, it still remains unascertained. Serum biomarkers can be a solution for this as they can be isolated in a less painful, more cost-effective, and minimally invasive manner. In this study, we shed light on the relevant role of multiple microRNAs (miRNAs) as potential biomarkers in breast cancer diagnosis. We monitored the expressional changes of 15 pre-selected miRNAs in a large cohort, including 65 patients with breast cancer and 42 healthy individuals. We performed thorough statistical analyses on the cohort sample set and determined the diagnostic accuracy of individual and multiple miRNAs. Our study reveals a potential improvement in diagnostics by implicating the monitoring of miR-15a+miR-16+miR-221 expression in breast cancer management. Full article

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18 pages, 1863 KB

Open AccessEditor’s ChoiceReview

The CXCL13/CXCR5 Immune Axis in Health and Disease—Implications for Intrathecal B Cell Activities in Neuroinflammation

by Christine Harrer, Ferdinand Otto, Richard Friedrich Radlberger, Tobias Moser, Georg Pilz, Peter Wipfler and Andrea Harrer

Cells 2022, 11(17), 2649; https://doi.org/10.3390/cells11172649 - 25 Aug 2022

Cited by 31 | Viewed by 10089

Abstract

The chemokine C-X-C- ligand 13 (CXCL13) is a major B cell chemoattractant to B cell follicles in secondary lymphoid organs (SLO) that proposedly recruits B cells to the cerebrospinal fluid (CSF) during neuroinflammation. CXCR5, the cognate receptor of CXCL13, is expressed on B [...] Read more.

The chemokine C-X-C- ligand 13 (CXCL13) is a major B cell chemoattractant to B cell follicles in secondary lymphoid organs (SLO) that proposedly recruits B cells to the cerebrospinal fluid (CSF) during neuroinflammation. CXCR5, the cognate receptor of CXCL13, is expressed on B cells and certain T cell subsets, in particular T follicular helper cells (Tfh cells), enabling them to follow CXCL13 gradients towards B cell follicles for spatial proximity, a prerequisite for productive T cell–B cell interaction. Tfh cells are essential contributors to B cell proliferation, differentiation, and high-affinity antibody synthesis and are required for germinal center formation and maintenance. Circulating Tfh cells (cTfh) have been observed in the peripheral blood and CSF. Furthermore, CXCL13/CXCR5-associated immune activities organize and shape adaptive B cell-related immune responses outside of SLO via the formation of ectopic lymphoid structures in inflamed tissues, including the central nervous system (CNS). This review summarizes the recent advances in our understanding of the CXCL13/CXCR5 immune axis and its role in vaccination, autoimmunity, and infection with a special focus on its relevance for intrathecal B cell activities in inflammatory CNS diseases. Full article

(This article belongs to the Special Issue Frontiers in Neuroinflammation)

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25 pages, 6296 KB

Open AccessEditor’s ChoiceArticle

The Proteome Signatures of Fibroblasts from Patients with Severe, Intermediate and Mild Spinal Muscular Atrophy Show Limited Overlap

by Sharon J. Brown, Rachel A. Kline, Silvia A. Synowsky, Sally L. Shirran, Ian Holt, Kelly A. Sillence, Peter Claus, Brunhilde Wirth, Thomas M. Wishart and Heidi R. Fuller

Cells 2022, 11(17), 2624; https://doi.org/10.3390/cells11172624 - 23 Aug 2022

Cited by 7 | Viewed by 4322

Abstract

Most research to characterise the molecular consequences of spinal muscular atrophy (SMA) has focused on SMA I. Here, proteomic profiling of skin fibroblasts from severe (SMA I), intermediate (SMA II), and mild (SMA III) patients, alongside age-matched controls, was conducted using SWATH mass [...] Read more.

Most research to characterise the molecular consequences of spinal muscular atrophy (SMA) has focused on SMA I. Here, proteomic profiling of skin fibroblasts from severe (SMA I), intermediate (SMA II), and mild (SMA III) patients, alongside age-matched controls, was conducted using SWATH mass spectrometry analysis. Differentially expressed proteomic profiles showed limited overlap across each SMA type, and variability was greatest within SMA II fibroblasts, which was not explained by SMN2 copy number. Despite limited proteomic overlap, enriched canonical pathways common to two of three SMA severities with at least one differentially expressed protein from the third included mTOR signalling, regulation of eIF2 and eIF4 signalling, and protein ubiquitination. Network expression clustering analysis identified protein profiles that may discriminate or correlate with SMA severity. From these clusters, the differential expression of PYGB (SMA I), RAB3B (SMA II), and IMP1 and STAT1 (SMA III) was verified by Western blot. All SMA fibroblasts were transfected with an SMN-enhanced construct, but only RAB3B expression in SMA II fibroblasts demonstrated an SMN-dependent response. The diverse proteomic profiles and pathways identified here pave the way for studies to determine their utility as biomarkers for patient stratification or monitoring treatment efficacy and for the identification of severity-specific treatments. Full article

(This article belongs to the Special Issue Proteomic Applications in Ageing and Neurodegenerative Conditions)

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18 pages, 5314 KB

Open AccessEditor’s ChoiceArticle

Pathogenetic Mechanisms Underlying Spinocerebellar Ataxia Type 3 Are Altered in Primary Oligodendrocyte Culture

by Kristen H. Schuster, Alexandra F. Putka and Hayley S. McLoughlin

Cells 2022, 11(16), 2615; https://doi.org/10.3390/cells11162615 - 22 Aug 2022

Cited by 9 | Viewed by 3756

Abstract

Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of [...] Read more.

Emerging evidence has implicated non-neuronal cells, particularly oligodendrocytes, in the pathophysiology of many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Spinocerebellar ataxia type 3 (SCA3). We recently demonstrated that cell-autonomous dysfunction of oligodendrocyte maturation is one of the of the earliest and most robust changes in vulnerable regions of the SCA3 mouse brain. However, the cell- and disease-specific mechanisms that underlie oligodendrocyte dysfunction remain poorly understood and are difficult to isolate in vivo. In this study, we used primary oligodendrocyte cultures to determine how known pathogenic SCA3 mechanisms affect this cell type. We isolated oligodendrocyte progenitor cells from 5- to 7-day-old mice that overexpress human mutant ATXN3 or lack mouse ATXN3 and differentiated them for up to 5 days in vitro. Utilizing immunocytochemistry, we characterized the contributions of ATXN3 toxic gain-of-function and loss-of-function in oligodendrocyte maturation, protein quality pathways, DNA damage signaling, and methylation status. We illustrate the utility of primary oligodendrocyte culture for elucidating cell-specific pathway dysregulation relevant to SCA3. Given recent work demonstrating disease-associated oligodendrocyte signatures in other neurodegenerative diseases, this novel model has broad applicability in revealing mechanistic insights of oligodendrocyte contribution to pathogenesis. Full article

(This article belongs to the Collection Spinocerebellar Ataxia (SCA): Molecular Mechanisms and Novel Treatment Strategies)

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15 pages, 2191 KB

Open AccessEditor’s ChoiceArticle

A Multi-Strain Probiotic Formulation Improves Intestinal Barrier Function by the Modulation of Tight and Adherent Junction Proteins

by Raffaella di Vito, Carmela Conte and Giovanna Traina

Cells 2022, 11(16), 2617; https://doi.org/10.3390/cells11162617 - 22 Aug 2022

Cited by 53 | Viewed by 8826

Abstract

In healthy individuals, tight junction proteins (TJPs) maintain the integrity of the intestinal barrier. Dysbiosis and increased intestinal permeability are observed in several diseases, such as inflammatory bowel disease. Many studies highlight the role of probiotics in preventing intestinal barrier dysfunction. The present [...] Read more.

In healthy individuals, tight junction proteins (TJPs) maintain the integrity of the intestinal barrier. Dysbiosis and increased intestinal permeability are observed in several diseases, such as inflammatory bowel disease. Many studies highlight the role of probiotics in preventing intestinal barrier dysfunction. The present study aims to investigate the effects of a commercially available probiotic formulation of L. rhamnosus LR 32, B. lactis BL 04, and B. longum BB 536 (Serobioma, Bromatech s.r.l., Milan, Italy) on TJPs and the integrity of the intestinal epithelial barrier, and the ability of this formulation to prevent lipopolysaccharide-induced, inflammation-associated damage. An in vitro model of the intestinal barrier was developed using a Caco-2 cell monolayer. The mRNA expression levels of the TJ genes were analyzed using real-time PCR. Changes in the amounts of proteins were assessed with Western blotting. The effect of Serobioma on the intestinal epithelial barrier function was assessed using transepithelial electrical resistance (TEER) measurements. The probiotic formulation tested in this study modulates the expression of TJPs and prevents inflammatory damage. Our findings provide new insights into the mechanisms by which probiotics are able to prevent damage to the gut epithelial barrier. Full article

(This article belongs to the Special Issue Gut Microbiota in Nutrition and Health)

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32 pages, 5494 KB

Open AccessEditor’s ChoiceArticle

Single Cell Analysis of Cultivated Fibroblasts from Chronic Pancreatitis and Pancreatic Cancer Patients

by Yoshiaki Sunami, Yijun Chen, Bogusz Trojanowicz, Matthias Sommerer, Monika Hämmerle, Roland Eils and Jörg Kleeff

Cells 2022, 11(16), 2583; https://doi.org/10.3390/cells11162583 - 19 Aug 2022

Cited by 5 | Viewed by 4618

Abstract

Cancer-associated fibroblasts (CAFs) play a major role in the progression and drug resistance of pancreatic cancer. Recent studies suggest that CAFs exhibit functional heterogeneity and distinct transcriptomic signatures in pancreatic cancer. Pancreatic fibroblasts also form an integral component in pancreatic diseases such as [...] Read more.

Cancer-associated fibroblasts (CAFs) play a major role in the progression and drug resistance of pancreatic cancer. Recent studies suggest that CAFs exhibit functional heterogeneity and distinct transcriptomic signatures in pancreatic cancer. Pancreatic fibroblasts also form an integral component in pancreatic diseases such as chronic pancreatitis named disease-associated fibroblasts (DAFs). However, intra-tumoral heterogeneity of CAFs in pancreatic cancer patients and their pivotal role in cancer-related mechanisms have not been fully elucidated. Further, it has not been elucidated whether CAF subtypes identified in pancreatic cancer also exist in chronic pancreatitis. In this study, we used primary isolated fibroblasts from pancreatic cancer and chronic pancreatitis patients using the outgrowth method. Single-cell RNA sequencing (scRNA-seq) was performed, and bioinformatics analysis identified highly variable genes, including factors associated with overall survival of pancreatic cancer patients. The majority of highly variable genes are involved in the cell cycle. Instead of previously classified myofibroblastic (myCAFs), inflammatory (iCAFs), and antigen-presenting (ap) CAFs, we identified a myCAFs-like subtype in all cases. Most interestingly, after cell cycle regression, we observed 135 highly variable genes commonly identified in chronic pancreatitis and pancreatic cancer patients. This study is the first to conduct scRNAseq and bioinformatics analyses to compare CAFs/DAFs from both chronic pancreatitis and pancreatic cancer patients. Further studies are required to select and identify stromal factors in DAFs from chronic pancreatitis cases, which are commonly expressed also in CAFs potentially contributing to pancreatic cancer development. Full article

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13 pages, 2474 KB

Open AccessEditor’s ChoiceArticle

Integrated Multi-Omics Signature Predicts Survival in Head and Neck Cancer

by Ilda Patrícia Ribeiro, Luísa Esteves, Francisco Caramelo, Isabel Marques Carreira and Joana Barbosa Melo

Cells 2022, 11(16), 2536; https://doi.org/10.3390/cells11162536 - 16 Aug 2022

Cited by 13 | Viewed by 2757

Abstract

Head and Neck Cancer (HNC) is characterized by phenotypic, biological, and clinical heterogeneity. Despite treatment modalities, approximately half of all patients will die of the disease. Several molecular biomarkers have been investigated, but until now, without clinical translation. Here, we identified an integrative [...] Read more.

Head and Neck Cancer (HNC) is characterized by phenotypic, biological, and clinical heterogeneity. Despite treatment modalities, approximately half of all patients will die of the disease. Several molecular biomarkers have been investigated, but until now, without clinical translation. Here, we identified an integrative nine-gene multi-omics signature correlated with HNC patients’ survival independently of relapses or metastasis development. This prognosis multi-omic signature comprises genes mapped in the chromosomes 1q, 3p, 8q, 17q, 19p, and 19q and encompasses alterations at copy number, gene expression, and methylation. Copy number alterations in LMCD1-A1S and GRM7, the methylation status of CEACAM19, KRT17, and ST18, and the expression profile of RPL29, UBA7, FCGR2C, and RPSAP58 can predict the HNC patients’ survival. The difference higher than two years observed in the survival of HNC patients that harbor this nine-gene multi-omics signature can represent a significant step forward to improve patients’ management and guide new therapeutic targets development. Full article

(This article belongs to the Special Issue Early Biomarkers of Cancer: Diagnosis and Progression)

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13 pages, 2934 KB

Open AccessEditor’s ChoiceArticle

Oxidative Stress Is Associated with Overgrowth in Drosophila l(3)mbt Mutant Imaginal Discs

by Paula Climent-Cantó, Cristina Molnar, Paula Santabárbara-Ruiz, Cristina Prieto, Josep F. Abril, Florenci Serras and Cayetano Gonzalez

Cells 2022, 11(16), 2542; https://doi.org/10.3390/cells11162542 - 16 Aug 2022

Cited by 1 | Viewed by 2992

Abstract

The loss-of-function conditions for an l(3)malignant brain tumour (l(3)mbt) in larvae reared at 29 °C results in malignant brain tumours and hyperplastic imaginal discs. Unlike the former that have been extensively characterised, little is known about the latter. Here we report [...] Read more.

The loss-of-function conditions for an l(3)malignant brain tumour (l(3)mbt) in larvae reared at 29 °C results in malignant brain tumours and hyperplastic imaginal discs. Unlike the former that have been extensively characterised, little is known about the latter. Here we report the results of a study of the hyperplastic l(3)mbt mutant wing imaginal discs. We identify the l(3)mbt wing disc tumour transcriptome and find it to include genes involved in reactive oxygen species (ROS) metabolism. Furthermore, we show the presence of oxidative stress in l(3)mbt hyperplastic discs, even in apoptosis-blocked conditions, but not in l(3)mbt brain tumours. We also find that chemically blocking oxidative stress in l(3)mbt wing discs reduces the incidence of wing disc overgrowths. Our results reveal the involvement of oxidative stress in l(3)mbt wing discs hyperplastic growth. Full article

(This article belongs to the Special Issue Research Advances in Invertebrate Experimental Models of Malignant Growth)

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21 pages, 6615 KB

Open AccessEditor’s ChoiceReview

Corneal Regeneration Using Adipose-Derived Mesenchymal Stem Cells

by Jorge L. Alió del Barrio, Ana De la Mata, María P. De Miguel, Francisco Arnalich-Montiel, Teresa Nieto-Miguel, Mona El Zarif, Marta Cadenas-Martín, Marina López-Paniagua, Sara Galindo, Margarita Calonge and Jorge L. Alió

Cells 2022, 11(16), 2549; https://doi.org/10.3390/cells11162549 - 16 Aug 2022

Cited by 42 | Viewed by 6426

Abstract

Adipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular [...] Read more.

Adipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular lineages, to show immunomodulatory properties, and to promote tissue regeneration by a paracrine action through the secretion of extracellular vesicles containing trophic factors. This secretome is currently being investigated as a potential source for a cell-free based regenerative therapy for human tissues, which would significantly reduce the involved costs, risks and law regulations, allowing for a broader application in real clinical practice. In the current article, we will review the existing preclinical and human clinical evidence regarding the use of such adipose-derived mesenchymal stem cells for the regeneration of the three main layers of the human cornea: the epithelium (derived from the surface ectoderm), the stroma (derived from the neural crest mesenchyme), and the endothelium (derived from the neural crest cells). Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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16 pages, 3108 KB

Open AccessEditor’s ChoiceArticle

Integration of Human Protein Sequence and Protein-Protein Interaction Data by Graph Autoencoder to Identify Novel Protein-Abnormal Phenotype Associations

by Yuan Liu, Ruirui He, Yingjie Qu, Yuan Zhu, Dianke Li, Xinping Ling, Simin Xia, Zhenqiu Li and Dong Li

Cells 2022, 11(16), 2485; https://doi.org/10.3390/cells11162485 - 10 Aug 2022

Cited by 7 | Viewed by 3354

Abstract

Understanding gene functions and their associated abnormal phenotypes is crucial in the prevention, diagnosis and treatment against diseases. The Human Phenotype Ontology (HPO) is a standardized vocabulary for describing the phenotype abnormalities associated with human diseases. However, the current HPO annotations are far [...] Read more.

Understanding gene functions and their associated abnormal phenotypes is crucial in the prevention, diagnosis and treatment against diseases. The Human Phenotype Ontology (HPO) is a standardized vocabulary for describing the phenotype abnormalities associated with human diseases. However, the current HPO annotations are far from completion, and only a small fraction of human protein-coding genes has HPO annotations. Thus, it is necessary to predict protein-phenotype associations using computational methods. Protein sequences can indicate the structure and function of the proteins, and interacting proteins are more likely to have same function. It is promising to integrate these features for predicting HPO annotations of human protein. We developed GraphPheno, a semi-supervised method based on graph autoencoders, which does not require feature engineering to capture deep features from protein sequences, while also taking into account the topological properties in the protein–protein interaction network to predict the relationships between human genes/proteins and abnormal phenotypes. Cross validation and independent dataset tests show that GraphPheno has satisfactory prediction performance. The algorithm is further confirmed on automatic HPO annotation for no-knowledge proteins under the benchmark of the second Critical Assessment of Functional Annotation, 2013–2014 (CAFA2), where GraphPheno surpasses most existing methods. Further bioinformatics analysis shows that predicted certain phenotype-associated genes using GraphPheno share similar biological properties with known ones. In a case study on the phenotype of abnormality of mitochondrial respiratory chain, top prioritized genes are validated by recent papers. We believe that GraphPheno will help to reveal more associations between genes and phenotypes, and contribute to the discovery of drug targets. Full article

(This article belongs to the Special Issue New Insights into Proteomics and Post-translational Modification of Proteins)

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11 pages, 2526 KB

Open AccessEditor’s ChoiceCommunication

PARA: A New Platform for the Rapid Assembly of gRNA Arrays for Multiplexed CRISPR Technologies

by Guoliang Yuan, Stanton Martin, Md Mahmudul Hassan, Gerald A. Tuskan and Xiaohan Yang

Cells 2022, 11(16), 2467; https://doi.org/10.3390/cells11162467 - 9 Aug 2022

Cited by 12 | Viewed by 4819

Abstract

Multiplexed CRISPR technologies have great potential for pathway engineering and genome editing. However, their applications are constrained by complex, laborious and time-consuming cloning steps. In this research, we developed a novel method, PARA, which allows for the one-step assembly of multiple guide RNAs [...] Read more.

Multiplexed CRISPR technologies have great potential for pathway engineering and genome editing. However, their applications are constrained by complex, laborious and time-consuming cloning steps. In this research, we developed a novel method, PARA, which allows for the one-step assembly of multiple guide RNAs (gRNAs) into a CRISPR vector with up to 18 gRNAs. Here, we demonstrate that PARA is capable of the efficient assembly of transfer RNA/Csy4/ribozyme-based gRNA arrays. To aid in this process and to streamline vector construction, we developed a user-friendly PARAweb tool for designing PCR primers and component DNA parts and simulating assembled gRNA arrays and vector sequences. Full article

(This article belongs to the Special Issue CRISPR/Cas9: From the Bacteria to Widespread Advanced Genome Editing Tools in Mammalian Cells)

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22 pages, 6182 KB

Open AccessEditor’s ChoiceArticle

Screening Biophysical Sensors and Neurite Outgrowth Actuators in Human Induced-Pluripotent-Stem-Cell-Derived Neurons

by Vaibhav P. Pai, Ben G. Cooper and Michael Levin

Cells 2022, 11(16), 2470; https://doi.org/10.3390/cells11162470 - 9 Aug 2022

Cited by 4 | Viewed by 4582

Abstract

All living cells maintain a charge distribution across their cell membrane (membrane potential) by carefully controlled ion fluxes. These bioelectric signals regulate cell behavior (such as migration, proliferation, differentiation) as well as higher-level tissue and organ patterning. Thus, voltage gradients represent an important [...] Read more.

All living cells maintain a charge distribution across their cell membrane (membrane potential) by carefully controlled ion fluxes. These bioelectric signals regulate cell behavior (such as migration, proliferation, differentiation) as well as higher-level tissue and organ patterning. Thus, voltage gradients represent an important parameter for diagnostics as well as a promising target for therapeutic interventions in birth defects, injury, and cancer. However, despite much progress in cell and molecular biology, little is known about bioelectric states in human stem cells. Here, we present simple methods to simultaneously track ion dynamics, membrane voltage, cell morphology, and cell activity (pH and ROS), using fluorescent reporter dyes in living human neurons derived from induced neural stem cells (hiNSC). We developed and tested functional protocols for manipulating ion fluxes, membrane potential, and cell activity, and tracking neural responses to injury and reinnervation in vitro. Finally, using morphology sensor, we tested and quantified the ability of physiological actuators (neurotransmitters and pH) to manipulate nerve repair and reinnervation. These methods are not specific to a particular cell type and should be broadly applicable to the study of bioelectrical controls across a wide range of combinations of models and endpoints. Full article

(This article belongs to the Special Issue Molecular Bioelectricity and Cell Behaviour)

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20 pages, 4849 KB

Open AccessEditor’s ChoiceArticle

Membrane Properties of Human Induced Pluripotent Stem Cell-Derived Cultured Red Blood Cells

by Claudia Bernecker, Eva Maria Matzhold, Dagmar Kolb, Afrim Avdili, Lisa Rohrhofer, Annika Lampl, Martin Trötzmüller, Heike Singer, Johannes Oldenburg, Peter Schlenke and Isabel Dorn

Cells 2022, 11(16), 2473; https://doi.org/10.3390/cells11162473 - 9 Aug 2022

Cited by 7 | Viewed by 5397

Abstract

Cultured red blood cells from human induced pluripotent stem cells (cRBC_iPSCs) are a promising source for future concepts in transfusion medicine. Before cRBC_iPSCs will have entrance into clinical or laboratory use, their functional properties and safety have to be carefully validated. Due to [...] Read more.

Cultured red blood cells from human induced pluripotent stem cells (cRBC_iPSCs) are a promising source for future concepts in transfusion medicine. Before cRBC_iPSCs will have entrance into clinical or laboratory use, their functional properties and safety have to be carefully validated. Due to the limitations of established culture systems, such studies are still missing. Improved erythropoiesis in a recently established culture system, closer simulating the physiological niche, enabled us to conduct functional characterization of enucleated cRBC_iPSCs with a focus on membrane properties. Morphology and maturation stage of cRBC_iPSCs were closer to native reticulocytes (nRETs) than to native red blood cells (nRBCs). Whereas osmotic resistance of cRBC_iPSCs was similar to nRETs, their deformability was slightly impaired. Since no obvious alterations in membrane morphology, lipid composition, and major membrane associated protein patterns were observed, reduced deformability might be caused by a more primitive nature of cRBC_iPSCs comparable to human embryonic- or fetal liver erythropoiesis. Blood group phenotyping of cRBC_iPSCs further confirmed the potency of cRBC_iPSCs as a prospective device in pre-transfusional routine diagnostics. Therefore, RBC membrane analyses obtained in this study underscore the overall prospects of cRBC_iPSCs for their future application in the field of transfusion medicine. Full article

(This article belongs to the Collection Advances in Red Blood Cells Research)

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19 pages, 2110 KB

Open AccessEditor’s ChoiceArticle

Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1

by Ying Jiang, Vitalyi Senyuk, Ke Ma, Hui Chen, Xiang Qin, Shun Li, Yiyao Liu, Saverio Gentile and Richard D. Minshall

Cells 2022, 11(15), 2461; https://doi.org/10.3390/cells11152461 - 8 Aug 2022

Cited by 10 | Viewed by 3599

Abstract

The prevention of metastasis is a central goal of cancer therapy. Caveolin-1 (Cav-1) is a structural membrane and scaffolding protein shown to be a key regulator of late-stage breast cancer metastasis. However, therapeutic strategies targeting Cav-1 are still lacking. Here, we demonstrate that [...] Read more.

The prevention of metastasis is a central goal of cancer therapy. Caveolin-1 (Cav-1) is a structural membrane and scaffolding protein shown to be a key regulator of late-stage breast cancer metastasis. However, therapeutic strategies targeting Cav-1 are still lacking. Here, we demonstrate that the pharmacological activation of potassium channel Kv11.1, which is uniquely expressed in MDA-MB-231 triple negative breast cancer cells (TNBCs) but not in normal MCF-10A cells, induces the dephosphorylation of Cav-1 Tyr-14 by promoting the Ca²⁺-dependent stimulation of protein tyrosine phosphatase 1B (PTP1B). Consequently, the dephosphorylation of Cav-1 resulted in its disassociation from β-catenin, which enabled the accumulation of β-catenin at cell borders, where it facilitated the formation of cell–cell adhesion complexes via interactions with R-cadherin and desmosomal proteins. Kv11.1 activation-dependent Cav-1 dephosphorylation induced with NS1643 also reduced cell migration and invasion, consistent with its ability to regulate focal adhesion dynamics. Thus, this study sheds light on a novel pharmacological mechanism of promoting Cav-1 dephosphorylation, which may prove to be effective at reducing metastasis and promoting contact inhibition. Full article

(This article belongs to the Collection Feature Papers in Cell Motility and Adhesion)

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12 pages, 2223 KB

Open AccessEditor’s ChoiceArticle

Spectral Library-Based Single-Cell Proteomics Resolves Cellular Heterogeneity

by Lakmini Senavirathna, Cheng Ma, Ru Chen and Sheng Pan

Cells 2022, 11(15), 2450; https://doi.org/10.3390/cells11152450 - 7 Aug 2022

Cited by 12 | Viewed by 4273

Abstract

Dissecting the proteome of cell types and states at single-cell resolution, while being highly challenging, has significant implications in basic science and biomedicine. Mass spectrometry (MS)-based single-cell proteomics represents an emerging technology for system-wide, unbiased profiling of proteins in single cells. However, significant [...] Read more.

Dissecting the proteome of cell types and states at single-cell resolution, while being highly challenging, has significant implications in basic science and biomedicine. Mass spectrometry (MS)-based single-cell proteomics represents an emerging technology for system-wide, unbiased profiling of proteins in single cells. However, significant challenges remain in analyzing an extremely small amount of proteins collected from a single cell, as a proteome-wide amplification of proteins is not currently feasible. Here, we report an integrated spectral library-based single-cell proteomics (SLB-SCP) platform that is ultrasensitive and well suited for a large-scale analysis. To overcome the low MS/MS signal intensity intrinsically associated with a single-cell analysis, this approach takes an alternative approach by extracting a breadth of information that specifically defines the physicochemical characteristics of a peptide from MS1 spectra, including monoisotopic mass, isotopic distribution, and retention time (hydrophobicity), and uses a spectral library for proteomic identification. This conceptually unique MS platform, coupled with the DIRECT sample preparation method, enabled identification of more than 2000 proteins in a single cell to distinguish different proteome landscapes associated with cellular types and heterogeneity. We characterized individual normal and cancerous pancreatic ductal cells (HPDE and PANC-1, respectively) and demonstrated the substantial difference in the proteomes between HPDE and PANC-1 at the single-cell level. A significant upregulation of multiple protein networks in cancer hallmarks was identified in the PANC-1 cells, functionally discriminating the PANC-1 cells from the HPDE cells. This integrated platform can be built on high-resolution MS and widely accepted proteomic software, making it possible for community-wide applications. Full article

(This article belongs to the Collection Deciphering the Proteome in Cell Biology and Diseases)

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15 pages, 2955 KB

Open AccessEditor’s ChoiceArticle

Cytosolic HMGB1 Mediates LPS-Induced Autophagy in Microglia by Interacting with NOD2 and Suppresses Its Proinflammatory Function

by Seung-Woo Kim, Sang-A Oh, Song-I Seol, Dashdulam Davaanyam and Ja-Kyeong Lee

Cells 2022, 11(15), 2410; https://doi.org/10.3390/cells11152410 - 4 Aug 2022

Cited by 17 | Viewed by 4211

Abstract

The high mobility group box 1 (HMGB1), a well-known danger-associated molecule pattern (DAMP) molecule, is a non-histone chromosomal protein localized in the nucleus under normal physiological conditions. HMGB1 exhibits diverse functions depending on its subcellular location. In the present study, we investigated the [...] Read more.

The high mobility group box 1 (HMGB1), a well-known danger-associated molecule pattern (DAMP) molecule, is a non-histone chromosomal protein localized in the nucleus under normal physiological conditions. HMGB1 exhibits diverse functions depending on its subcellular location. In the present study, we investigated the role of HMGB1-induced autophagy in the lipopolysaccharide (LPS)-treated BV2 microglial cell line in mediating the transition between the inflammatory and autophagic function of the nucleotide-binding oligomerization domain-containing 2 (NOD2), a cytoplasmic pattern-recognition receptor. The induction of the microtubule-associated protein 1 light chain 3 (LC3), an autophagy biomarker, was detected slowly in BV2 cells after the LPS treatment, and peak induction was detected at 12 h. Under these conditions, NOD2 level was significantly increased and the binding between HMGB1 and NOD2 and between HMGB1 and ATG16L1 was markedly enhanced and the temporal profiles of the LC3II induction and HMGB1-NOD2 and HMGB1-ATG16L1 complex formation coincided with the cytosolic accumulation of HMGB1. The LPS-mediated autophagy induction was significantly suppressed in BV2 cells after HMGB1 or NOD2 knock-down (KD), indicating that HMGB1 contributes to NOD2-mediated autophagy induction in microglia. Moreover, NOD2-RIP2 interaction-mediated pro-inflammatory cytokine induction and NF-κB activity were significantly enhanced in BV2 cells after HMGB1 KD, indicating that HMGB1 plays a critical role in the modulation of NOD2 function between pro-inflammation and pro-autophagy in microglia. The effects of the cell-autonomous pro-autophagic pathway operated by cytoplasmic HMGB1 may be beneficial, whereas those from the paracrine pro-inflammatory pathway executed by extracellularly secreted HMGB1 can be detrimental. Thus, the overall functional significance of HMGB1-induced autophagy is different, depending on its temporal activity. Full article

(This article belongs to the Special Issue Autophagy in the Nervous System)

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47 pages, 7312 KB

Open AccessEditor’s ChoiceReview

BMP Signaling Pathway in Dentin Development and Diseases

by Mengmeng Liu, Graham Goldman, Mary MacDougall and Shuo Chen

Cells 2022, 11(14), 2216; https://doi.org/10.3390/cells11142216 - 16 Jul 2022

Cited by 58 | Viewed by 14667

Abstract

BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction [...] Read more.

BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described. Full article

(This article belongs to the Special Issue Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases)

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15 pages, 1386 KB

Open AccessEditor’s ChoiceReview

Recent Advances in Improving Gene-Editing Specificity through CRISPR–Cas9 Nuclease Engineering

by Xiaoqiang Huang, Dongshan Yang, Jifeng Zhang, Jie Xu and Y. Eugene Chen

Cells 2022, 11(14), 2186; https://doi.org/10.3390/cells11142186 - 13 Jul 2022

Cited by 36 | Viewed by 8051

Abstract

CRISPR–Cas9 is the state-of-the-art programmable genome-editing tool widely used in many areas. For safe therapeutic applications in clinical medicine, its off-target effect must be dramatically minimized. In recent years, extensive studies have been conducted to improve the gene-editing specificity of the most popular [...] Read more.

CRISPR–Cas9 is the state-of-the-art programmable genome-editing tool widely used in many areas. For safe therapeutic applications in clinical medicine, its off-target effect must be dramatically minimized. In recent years, extensive studies have been conducted to improve the gene-editing specificity of the most popular CRISPR–Cas9 nucleases using different strategies. In this review, we summarize and discuss these strategies and achievements, with a major focus on improving the gene-editing specificity through Cas9 protein engineering. Full article

(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research)

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17 pages, 3998 KB

Open AccessEditor’s ChoiceArticle

Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing

by Stuart J. Mills, Parinaz Ahangar, Hannah M. Thomas, Benjamin R. Hofma, Rachael Z. Murray and Allison J. Cowin

Cells 2022, 11(14), 2192; https://doi.org/10.3390/cells11142192 - 13 Jul 2022

Cited by 12 | Viewed by 2977

Abstract

TLR4 plays a pivotal role in orchestrating inflammation and tissue repair. Its expression has finally been balanced to initiate the early, robust immune response necessary for efficient repair without excessively amplifying and prolonging inflammation, which impairs healing. Studies show Flightless I (Flii) is [...] Read more.

TLR4 plays a pivotal role in orchestrating inflammation and tissue repair. Its expression has finally been balanced to initiate the early, robust immune response necessary for efficient repair without excessively amplifying and prolonging inflammation, which impairs healing. Studies show Flightless I (Flii) is an immunomodulator that negatively regulates macrophage TLR4 signalling. Using macrophages from Flii^+/−, WT, and Flii^Tg/Tg mice, we have shown that elevated Flii reduces early TLR4 surface expression, delaying and reducing subsequent TNF secretions. In contrast, reduced Flii increases surface TLR4, leading to an earlier robust TNF peak. In Flii^+/− mice, TLR4 levels peak earlier during wound repair, and overall healing is accelerated. Fewer neutrophils, monocytes and macrophages are recruited to Flii^+/− wounds, leading to fewer TNF-positive macrophages, alongside an early peak and a robust shift to M2 anti-inflammatory, reparative Ym1⁺ and IL-10⁺ macrophages. Importantly, in diabetic mice, high Flii levels are found in plasma and unwounded skin, with further increases observed in their wounds, which have impaired healing. Lowering Flii in diabetic mice results in an earlier shift to M2 macrophages and improved healing. Overall, this suggests Flii regulation of TLR4 reduces early inflammation and decreases the M2 macrophage phenotype, leading to impaired healing. Full article

(This article belongs to the Special Issue The Cell Biology and Immunology of Wound Healing)

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14 pages, 2440 KB

Open AccessEditor’s ChoiceArticle

CAR T-Cell Targeting of Macrophage Colony-Stimulating Factor Receptor

by Daniela Yordanova Achkova, Richard Esmond Beatson and John Maher

Cells 2022, 11(14), 2190; https://doi.org/10.3390/cells11142190 - 13 Jul 2022

Cited by 7 | Viewed by 3754

Abstract

Macrophage colony-stimulating factor receptor (M-CSFR) is found in cells of the mononuclear phagocyte lineage and is aberrantly expressed in a range of tumours, in addition to tumour-associated macrophages. Consequently, a variety of cancer therapies directed against M-CSFR are under development. We set out [...] Read more.

Macrophage colony-stimulating factor receptor (M-CSFR) is found in cells of the mononuclear phagocyte lineage and is aberrantly expressed in a range of tumours, in addition to tumour-associated macrophages. Consequently, a variety of cancer therapies directed against M-CSFR are under development. We set out to engineer chimeric antigen receptors (CARs) that employ the natural ligands of this receptor, namely M-CSF or interleukin (IL)-34, to achieve specificity for M-CSFR-expressing target cells. Both M-CSF and IL-34 bind to overlapping regions of M-CSFR, although affinity of IL-34 is significantly greater than that of M-CSF. Matched second- and third-generation CARs targeted using M-CSF or IL-34 were expressed in human T-cells using the SFG retroviral vector. We found that both M-CSF- and IL-34-containing CARs enable T-cells to mediate selective destruction of tumour cells that express enforced or endogenous M-CSFR, accompanied by production of both IL-2 and interferon (IFN)-γ. Although they contain an additional co-stimulatory module, third-generation CARs did not outperform second-generation CARs. M-CSF-containing CARs mediated enhanced cytokine production and cytolytic activity compared to IL-34-containing CARs. These data demonstrate the feasibility of targeting M-CSFR using ligand-based CARs and raise the possibility that the low picomolar affinity of IL-34 for M-CSFR is detrimental to CAR function. Full article

(This article belongs to the Section Cell and Gene Therapy)

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20 pages, 4731 KB

Open AccessEditor’s ChoiceArticle

CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints

by Martin Böttcher, Romy Böttcher-Loschinski, Sascha Kahlfuss, Michael Aigner, Andreas Gießl, Andreas Mackensen, Ursula Schlötzer-Schrehardt, Thomas Tüting, Heiko Bruns and Dimitrios Mougiakakos

Cells 2022, 11(14), 2176; https://doi.org/10.3390/cells11142176 - 12 Jul 2022

Cited by 19 | Viewed by 4828

Abstract

Background: Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of malignant B-cells and multiple immune defects. This leads, among others, to severe infectious complications and inefficient immune surveillance. T-cell deficiencies in CLL include enhanced immune(-metabolic) exhaustion, impaired activation and cytokine production, [...] Read more.

Background: Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of malignant B-cells and multiple immune defects. This leads, among others, to severe infectious complications and inefficient immune surveillance. T-cell deficiencies in CLL include enhanced immune(-metabolic) exhaustion, impaired activation and cytokine production, and immunological synapse malformation. Several studies have meanwhile reported CLL-cell–T-cell interactions that culminate in T-cell dysfunction. However, the complex entirety of their interplay is incompletely understood. Here, we focused on the impact of CLL cell-derived vesicles (EVs), which are known to exert immunoregulatory effects, on T-cell function. Methods: We characterized EVs secreted by CLL-cells and determined their influence on T-cells in terms of survival, activation, (metabolic) fitness, and function. Results: We found that CLL-EVs hamper T-cell viability, proliferation, activation, and metabolism while fostering their exhaustion and formation of regulatory T-cell subsets. A detailed analysis of the CLL-EV cargo revealed an abundance of immunological checkpoints (ICs) that could explain the detected T-cell dysregulations. Conclusions: The identification of a variety of ICs loaded on CLL-EVs may account for T-cell defects in CLL patients and could represent a barrier for immunotherapies such as IC blockade or adoptive T-cell transfer. Our findings could pave way for improving antitumor immunity by simultaneously targeting EV formation or multiple ICs. Full article

(This article belongs to the Collection Immuno-Metabolic Crosstalk in Oncogenesis)

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18 pages, 398 KB

Open AccessEditor’s ChoiceReview

Progress and Setbacks in Translating a Decade of Ferroptosis Research into Clinical Practice

by Friedrich Alexander von Samson-Himmelstjerna, Benedikt Kolbrink, Theresa Riebeling, Ulrich Kunzendorf and Stefan Krautwald

Cells 2022, 11(14), 2134; https://doi.org/10.3390/cells11142134 - 6 Jul 2022

Cited by 8 | Viewed by 3657

Abstract

Ten years after its initial description, ferroptosis has emerged as the most intensely studied entity among the non-apoptotic forms of regulated cell death. The molecular features of ferroptotic cell death and its functional role have been characterized in vitro and in an ever-growing [...] Read more.

Ten years after its initial description, ferroptosis has emerged as the most intensely studied entity among the non-apoptotic forms of regulated cell death. The molecular features of ferroptotic cell death and its functional role have been characterized in vitro and in an ever-growing number of animal studies, demonstrating that it exerts either highly detrimental or, depending on the context, occasionally beneficial effects on the organism. Consequently, two contrary therapeutic approaches are being explored to exploit our detailed understanding of this cell death pathway: the inhibition of ferroptosis to limit organ damage in disorders such as drug-induced toxicity or ischemia-reperfusion injury, and the induction of ferroptosis in cancer cells to ameliorate anti-tumor strategies. However, the path from basic science to clinical utility is rocky. Emphasizing ferroptosis inhibition, we review the success and failures thus far in the translational process from basic research in the laboratory to the treatment of patients. Full article

(This article belongs to the Special Issue Cell Metabolism and Oxidative Stress in the Process of Ferroptosis in Different Human Disease)

14 pages, 1649 KB

Open AccessEditor’s ChoiceArticle

Formation of Lymphoma Hybrid Spheroids and Drug Testing in Real Time with the Use of Fluorescence Optical Tweezers

by Kamila Duś-Szachniewicz, Katarzyna Gdesz-Birula, Emilia Nowosielska, Piotr Ziółkowski and Sławomir Drobczyński

Cells 2022, 11(13), 2113; https://doi.org/10.3390/cells11132113 - 5 Jul 2022

Cited by 7 | Viewed by 3381

Abstract

Interactions between stromal and lymphoma cells in the bone marrow are closely related to drug resistance and therapy failure. Physiologically relevant pre-clinical three-dimensional (3D) models recapitulating lymphoma microenvironmental complexity do not currently exist. In this study, we proposed a scheme for optically controlled [...] Read more.

Interactions between stromal and lymphoma cells in the bone marrow are closely related to drug resistance and therapy failure. Physiologically relevant pre-clinical three-dimensional (3D) models recapitulating lymphoma microenvironmental complexity do not currently exist. In this study, we proposed a scheme for optically controlled hybrid lymphoma spheroid formation with the use of optical tweezers (OT). Following the preparation of stromal spheroids using agarose hydrogel, two aggressive non-Hodgkin lymphoma B-cell lines, Ri-1 (DLBCL) and Raji (Burkitt lymphoma), were used to conduct multi-cellular spheroid formation driven by in-house-developed fluorescence optical tweezers. Importantly, the newly formed hybrid spheroid preserved the 3D architecture for the next 24 h. Our model was successfully used for the evaluation of the influence of the anticancer agents doxorubicin (DOX), ibrutinib (IBR), and AMD3100 (plerixafor) on the adhesive properties of lymphoma cells. Importantly, our study revealed that a co-treatment of DOX and IBR with AMD3100 affects the adhesion of B-NHL lymphoma cells. Full article

(This article belongs to the Special Issue In Vitro Model for Micro and Nano Technologies)

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11 pages, 397 KB

Open AccessEditor’s ChoiceArticle

ProB-Site: Protein Binding Site Prediction Using Local Features

by Sharzil Haris Khan, Hilal Tayara and Kil To Chong

Cells 2022, 11(13), 2117; https://doi.org/10.3390/cells11132117 - 5 Jul 2022

Cited by 16 | Viewed by 6584

Abstract

Protein–protein interactions (PPIs) are responsible for various essential biological processes. This information can help develop a new drug against diseases. Various experimental methods have been employed for this purpose; however, their application is limited by their cost and time consumption. Alternatively, computational methods [...] Read more.

Protein–protein interactions (PPIs) are responsible for various essential biological processes. This information can help develop a new drug against diseases. Various experimental methods have been employed for this purpose; however, their application is limited by their cost and time consumption. Alternatively, computational methods are considered viable means to achieve this crucial task. Various techniques have been explored in the literature using the sequential information of amino acids in a protein sequence, including machine learning and deep learning techniques. The current efficiency of interaction-site prediction still has growth potential. Hence, a deep neural network-based model, ProB-site, is proposed. ProB-site utilizes sequential information of a protein to predict its binding sites. The proposed model uses evolutionary information and predicted structural information extracted from sequential information of proteins, generating three unique feature sets for every amino acid in a protein sequence. Then, these feature sets are fed to their respective sub-CNN architecture to acquire complex features. Finally, the acquired features are concatenated and classified using fully connected layers. This methodology performed better than state-of-the-art techniques because of the selection of the best features and contemplation of local information of each amino acid. Full article

(This article belongs to the Special Issue New Insights into Proteomics and Post-translational Modification of Proteins)

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21 pages, 13676 KB

Open AccessEditor’s ChoiceArticle

Activation of Autophagic Flux Maintains Mitochondrial Homeostasis during Cardiac Ischemia/Reperfusion Injury

by Lihao He, Yuxin Chu, Jing Yang, Jin He, Yutao Hua, Yunxi Chen, Gloria Benavides, Glenn C. Rowe, Lufang Zhou, Scott Ballinger, Victor Darley-Usmar, Martin E. Young, Sumanth D. Prabhu, Palaniappan Sethu, Yingling Zhou, Cheng Zhang and Min Xie

Cells 2022, 11(13), 2111; https://doi.org/10.3390/cells11132111 - 4 Jul 2022

Cited by 19 | Viewed by 4059

Abstract

Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing [...] Read more.

Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing peptide, Tat-Beclin 1 (TB), reduces infarct size when administered at the time of reperfusion. However, since SAHA affects multiple pathways in addition to inducing autophagy, whether autophagic flux induced by TB maintains mitochondrial homeostasis during ischemia/reperfusion (I/R) injury is unknown. We tested whether the augmentation of autophagic flux by TB has cardioprotection by preserving mitochondrial homeostasis both in vitro and in vivo. Wild-type mice were randomized into two groups: Tat-Scrambled (TS) peptide as the control and TB as the experimental group. Mice were subjected to I/R surgery (45 min coronary ligation, 24 h reperfusion). Autophagic flux, mitochondrial DNA (mtDNA), mitochondrial morphology, and mitochondrial dynamic genes were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were treated with a simulated I/R injury to verify cardiomyocyte specificity. The essential autophagy gene, ATG7, conditional cardiomyocyte-specific knockout (ATG7 cKO) mice, and isolated adult mouse ventricular myocytes (AMVMs) were used to evaluate the dependency of autophagy in adult cardiomyocytes. In NRVMs subjected to I/R, TB increased autophagic flux, mtDNA content, mitochondrial function, reduced reactive oxygen species (ROS), and mtDNA damage. Similarly, in the infarct border zone of the mouse heart, TB induced autophagy, increased mitochondrial size and mtDNA content, and promoted the expression of PGC1α and mitochondrial dynamic genes. Conversely, loss of ATG7 in AMVMs and in the myocardium of ATG7 cKO mice abolished the beneficial effects of TB on mitochondrial homeostasis. Thus, autophagic flux is a sufficient and essential process to mitigate myocardial reperfusion injury by maintaining mitochondrial homeostasis and partly by inducing PGC1α-mediated mitochondrial biogenesis. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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31 pages, 12265 KB

Open AccessEditor’s ChoiceReview

Mechanisms of Sperm–Egg Interactions: What Ascidian Fertilization Research Has Taught Us

by Hitoshi Sawada and Takako Saito

Cells 2022, 11(13), 2096; https://doi.org/10.3390/cells11132096 - 1 Jul 2022

Cited by 12 | Viewed by 5570

Abstract

Fertilization is an essential process in terrestrial organisms for creating a new organism with genetic diversity. Before gamete fusion, several steps are required to achieve successful fertilization. Animal spermatozoa are first activated and attracted to the eggs by egg-derived chemoattractants. During the sperm [...] Read more.

Fertilization is an essential process in terrestrial organisms for creating a new organism with genetic diversity. Before gamete fusion, several steps are required to achieve successful fertilization. Animal spermatozoa are first activated and attracted to the eggs by egg-derived chemoattractants. During the sperm passage of the egg’s extracellular matrix or upon the sperm binding to the proteinaceous egg coat, the sperm undergoes an acrosome reaction, an exocytosis of acrosome. In hermaphrodites such as ascidians, the self/nonself recognition process occurs when the sperm binds to the egg coat. The activated or acrosome-reacted spermatozoa penetrate through the proteinaceous egg coat. The extracellular ubiquitin–proteasome system, the astacin-like metalloproteases, and the trypsin-like proteases play key roles in this process in ascidians. In the present review, we summarize our current understanding and perspectives on gamete recognition and egg coat lysins in ascidians and consider the general mechanisms of fertilization in animals and plants. Full article

(This article belongs to the Special Issue Ubiquitin–Proteasome System and Small Protein Modifiers in Gametogenesis and Fertility)

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20 pages, 6818 KB

Open AccessEditor’s ChoiceArticle

Chronic Fatty Acid Depletion Induces Uncoupling Protein 1 (UCP1) Expression to Coordinate Mitochondrial Inducible Proton Leak in a Human-Brown-Adipocyte Model

by Yukimasa Takeda and Ping Dai

Cells 2022, 11(13), 2038; https://doi.org/10.3390/cells11132038 - 27 Jun 2022

Cited by 6 | Viewed by 4374

Abstract

Thermogenic brown fat contributes to metabolic health in adult humans. Obese conditions are known to repress adipose-tissue browning and its activity. Herein, we found that chronic fatty acid (FA) depletion induced uncoupling protein 1 (UCP1) expression in the chemical-compound-induced brown adipocytes (ciBAs). The [...] Read more.

Thermogenic brown fat contributes to metabolic health in adult humans. Obese conditions are known to repress adipose-tissue browning and its activity. Herein, we found that chronic fatty acid (FA) depletion induced uncoupling protein 1 (UCP1) expression in the chemical-compound-induced brown adipocytes (ciBAs). The ciBAs, converted from human dermal fibroblasts under FA-free conditions, had low intracellular triglyceride levels and strongly activated UCP1 expression. Prolonged treatment with carnitine also reduced triglyceride accumulation and induced UCP1 expression. Transcriptome analysis revealed that the UCP1 induction was accompanied by the activation of lipid metabolic genes. The FA-depleted conditions repressed mitochondrial proton-leak activity and mitochondrial membrane potential (MMP), despite maintaining a high UCP1 expression. The evidence suggested that UCP1 expression was induced to compensate for the proton-leak activity under low MMP. Our study reports a regulatory mechanism underlying UCP1 expression and mitochondrial-energy status in human brown adipocytes under different nutritional conditions. Full article

(This article belongs to the Section Cellular Metabolism)

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23 pages, 1941 KB

Open AccessEditor’s ChoiceReview

The Good and the Bad: Monocytes’ and Macrophages’ Diverse Functions in Inflammation

by Judith Austermann, Johannes Roth and Katarzyna Barczyk-Kahlert

Cells 2022, 11(12), 1979; https://doi.org/10.3390/cells11121979 - 20 Jun 2022

Cited by 128 | Viewed by 14524

Abstract

Monocytes and macrophages are central players of the innate immune response and play a pivotal role in the regulation of inflammation. Thereby, they actively participate in all phases of the immune response, from initiating inflammation and triggering the adaptive immune response, through to [...] Read more.

Monocytes and macrophages are central players of the innate immune response and play a pivotal role in the regulation of inflammation. Thereby, they actively participate in all phases of the immune response, from initiating inflammation and triggering the adaptive immune response, through to the clearance of cell debris and resolution of inflammation. In this review, we described the mechanisms of monocyte and macrophage adaptation to rapidly changing microenvironmental conditions and discussed different forms of macrophage polarization depending on the environmental cues or pathophysiological condition. Therefore, special focus was placed on the tight regulation of the pro- and anti-inflammatory immune response, and the diverse functions of S100A8/S100A9 proteins and the scavenger receptor CD163 were highlighted, respectively. We paid special attention to the function of pro- and anti-inflammatory macrophages under pathological conditions. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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20 pages, 2000 KB

Open AccessEditor’s ChoiceReview

Platelets at the Crossroads of Pro-Inflammatory and Resolution Pathways during Inflammation

by Nadine Ludwig, Annika Hilger, Alexander Zarbock and Jan Rossaint

Cells 2022, 11(12), 1957; https://doi.org/10.3390/cells11121957 - 17 Jun 2022

Cited by 56 | Viewed by 10333

Abstract

Platelets are among the most abundant cells in the mammalian circulation. Classical platelet functions in hemostasis and wound healing have been intensively explored and are generally accepted. During the past decades, the research focus broadened towards their participation in immune-modulatory events, including pro-inflammatory [...] Read more.

Platelets are among the most abundant cells in the mammalian circulation. Classical platelet functions in hemostasis and wound healing have been intensively explored and are generally accepted. During the past decades, the research focus broadened towards their participation in immune-modulatory events, including pro-inflammatory and, more recently, inflammatory resolution processes. Platelets are equipped with a variety of abilities enabling active participation in immunological processes. Toll-like receptors mediate the recognition of pathogens, while the release of granule contents and microvesicles promotes direct pathogen defense and an interaction with leukocytes. Platelets communicate and physically interact with neutrophils, monocytes and a subset of lymphocytes via soluble mediators and surface adhesion receptors. This interaction promotes leukocyte recruitment, migration and extravasation, as well as the initiation of effector functions, such as the release of extracellular traps by neutrophils. Platelet-derived prostaglandin E2, C-type lectin-like receptor 2 and transforming growth factor β modulate inflammatory resolution processes by promoting the synthesis of pro-resolving mediators while reducing pro-inflammatory ones. Furthermore, platelets promote the differentiation of CD4⁺ T cells in T helper and regulatory T cells, which affects macrophage polarization. These abilities make platelets key players in inflammatory diseases such as pneumonia and the acute respiratory distress syndrome, including the pandemic coronavirus disease 2019. This review focuses on recent findings in platelet-mediated immunity during acute inflammation. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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20 pages, 1468 KB

Open AccessEditor’s ChoiceReview

Genetically Encoded ATP Biosensors for Direct Monitoring of Cellular ATP Dynamics

by Donnell White III and Qinglin Yang

Cells 2022, 11(12), 1920; https://doi.org/10.3390/cells11121920 - 14 Jun 2022

Cited by 27 | Viewed by 7502

Abstract

Adenosine 5′-triphosphate, or ATP, is the primary molecule for storing and transferring energy in cells. ATP is mainly produced via oxidative phosphorylation in mitochondria, and to a lesser extent, via glycolysis in the cytosol. In general, cytosolic glycolysis is the primary ATP producer [...] Read more.

Adenosine 5′-triphosphate, or ATP, is the primary molecule for storing and transferring energy in cells. ATP is mainly produced via oxidative phosphorylation in mitochondria, and to a lesser extent, via glycolysis in the cytosol. In general, cytosolic glycolysis is the primary ATP producer in proliferative cells or cells subjected to hypoxia. On the other hand, mitochondria produce over 90% of cellular ATP in differentiated cells under normoxic conditions. Under pathological conditions, ATP demand rises to meet the needs of biosynthesis for cellular repair, signaling transduction for stress responses, and biochemical processes. These changes affect how mitochondria and cytosolic glycolysis function and communicate. Mitochondria undergo remodeling to adapt to the imbalanced demand and supply of ATP. Otherwise, a severe ATP deficit will impair cellular function and eventually cause cell death. It is suggested that ATP from different cellular compartments can dynamically communicate and coordinate to adapt to the needs in each cellular compartment. Thus, a better understanding of ATP dynamics is crucial to revealing the differences in cellular metabolic processes across various cell types and conditions. This requires innovative methodologies to record real-time spatiotemporal ATP changes in subcellular regions of living cells. Over the recent decades, numerous methods have been developed and utilized to accomplish this task. However, this is not an easy feat. This review evaluates innovative genetically encoded biosensors available for visualizing ATP in living cells, their potential use in the setting of human disease, and identifies where we could improve and expand our abilities. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Cardiovascular Disease)

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15 pages, 2526 KB

Open AccessEditor’s ChoiceArticle

Ice Control during Cryopreservation of Heart Valves and Maintenance of Post-Warming Cell Viability

by Kelvin G. M. Brockbank, John C. Bischof, Zhenzhen Chen, Elizabeth D. Greene, Zhe Gao and Lia H. Campbell

Cells 2022, 11(12), 1856; https://doi.org/10.3390/cells11121856 - 7 Jun 2022

Cited by 11 | Viewed by 3407

Abstract

Heart valve cryopreservation was employed as a model for the development of complex tissue preservation methods based upon vitrification and nanowarming. Porcine heart valves were loaded with cryoprotectant formulations step wise and vitrified in 1–30 mL cryoprotectant formulations ± Fe nanoparticles ± 0.6 [...] Read more.

Heart valve cryopreservation was employed as a model for the development of complex tissue preservation methods based upon vitrification and nanowarming. Porcine heart valves were loaded with cryoprotectant formulations step wise and vitrified in 1–30 mL cryoprotectant formulations ± Fe nanoparticles ± 0.6 M disaccharides, cooled to −100 °C, and stored at −135 °C. Nanowarming was performed in a single ~100 s step by inductive heating within a magnetic field. Controls consisted of fresh and convection-warmed vitrified heart valves without nanoparticles. After washing, cell viability was assessed by metabolic assay. The nanowarmed leaflets were well preserved, with a viability similar to untreated fresh leaflets over several days post warming. The convection-warmed leaflet viability was not significantly different than that of the nanowarmed leaflets immediately after rewarming; however, a significantly higher nanowarmed leaflet viability (p < 0.05) was observed over time in vitro. In contrast, the associated artery and fibrous cardiac muscle were at best 75% viable, and viability decreased over time in vitro. Supplementation of lower concentration cryoprotectant formulations with disaccharides promoted viability. Thicker tissues benefited from longer-duration cryoprotectant loading steps. The best outcomes included a post-warming incubation step with α-tocopherol and an apoptosis inhibitor, Q-VD-OPH. This work demonstrates progress in the control of ice formation and cytotoxicity hurdles for the preservation of complex tissues. Full article

(This article belongs to the Special Issue Biobanking of Engineered and Natural Tissues)

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15 pages, 805 KB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

by Qianman Peng, Dan Shan, Kui Cui, Kathryn Li, Bo Zhu, Hao Wu, Beibei Wang, Scott Wong, Vikram Norton, Yunzhou Dong, Yao Wei Lu, Changcheng Zhou and Hong Chen

Cells 2022, 11(11), 1834; https://doi.org/10.3390/cells11111834 - 3 Jun 2022

Cited by 38 | Viewed by 8040

Abstract

Endothelial-to-mesenchymal transition (EndoMT) is the process of endothelial cells progressively losing endothelial-specific markers and gaining mesenchymal phenotypes. In the normal physiological condition, EndoMT plays a fundamental role in forming the cardiac valves of the developing heart. However, EndoMT contributes to the development of [...] Read more.

Endothelial-to-mesenchymal transition (EndoMT) is the process of endothelial cells progressively losing endothelial-specific markers and gaining mesenchymal phenotypes. In the normal physiological condition, EndoMT plays a fundamental role in forming the cardiac valves of the developing heart. However, EndoMT contributes to the development of various cardiovascular diseases (CVD), such as atherosclerosis, valve diseases, fibrosis, and pulmonary arterial hypertension (PAH). Therefore, a deeper understanding of the cellular and molecular mechanisms underlying EndoMT in CVD should provide urgently needed insights into reversing this condition. This review summarizes a 30-year span of relevant literature, delineating the EndoMT process in particular, key signaling pathways, and the underlying regulatory networks involved in CVD. Full article

(This article belongs to the Collection Cellular and Molecular Mechanisms of Atherosclerosis)

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16 pages, 3259 KB

Open AccessEditor’s ChoiceArticle

Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells

by Kamalnath S. Rajagopalan, Logan M. Glasstetter, Xiang-Yang Zhu, Roman Thaler, Hui Tang, Kyra L. Jordan, Ishran M. Saadiq, Sandra M. Herrmann, Alejandro R. Chade, Maria V. Irazabal, Lilach O. Lerman and Alfonso Eirin

Cells 2022, 11(11), 1803; https://doi.org/10.3390/cells11111803 - 31 May 2022

Cited by 10 | Viewed by 3077

Abstract

Background: Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells endowed with progenitor-like characteristics to repair injured parenchymal cells. STCs may be damaged and rendered ineffective by renal artery stenosis (RAS), but the underlying processes remain unclear. We hypothesized that RAS alters the [...] Read more.

Background: Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells endowed with progenitor-like characteristics to repair injured parenchymal cells. STCs may be damaged and rendered ineffective by renal artery stenosis (RAS), but the underlying processes remain unclear. We hypothesized that RAS alters the epigenetic landscape on DNA and the ensuing gene transcriptional profile of swine STCs. Methods: CD24+/CD133+ STCs were isolated from pig kidneys after 10 weeks of RAS or sham (n = 3 each) and their whole 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles were examined by 5mC and 5hmC immunoprecipitation sequencing (MeDIP-/hMeDIP-seq, respectively). A subsequent integrated (MeDIP/hMeDIP-seq/mRNA-seq) analysis was performed by comparing all online available gene sets using Gene Set Enrichment Analysis. Apoptosis, proteolysis, and mitochondrial structure and function were subsequently evaluated in vitro. Results: Differential expression (DE) analysis revealed 239 genes with higher and 236 with lower 5mC levels and 275 genes with higher and 315 with lower 5hmC levels in RAS-STCs compared to Normal-STCs (fold change ≥1.4 or ≤0.7, p ≤ 0.05). Integrated MeDIP-/hMeDIP-seq/mRNA-seq analysis identified several overlapping (DE-5mC/mRNA and DE-5hmC/mRNA levels) genes primarily implicated in apoptosis, proteolysis, and mitochondrial functions. Furthermore, RAS-STCs exhibited decreased apoptosis, mitochondrial matrix density, and ATP production, and increased intracellular amino acid concentration and ubiquitin expression. Conclusions: Renal ischemia induces epigenetic changes in apoptosis-, proteolysis-, and mitochondria-related genes, which correlate with alterations in the transcriptomic profile and corresponding function of swine STCs. These observations may contribute to developing novel targeted interventions to preserve the reparative potency of STCs in renal disease. Full article

(This article belongs to the Special Issue Mitochondrial Functions in Stem Cells)

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26 pages, 3884 KB

Open AccessEditor’s ChoiceArticle

Drought Tolerance Strategies and Autophagy in Resilient Wheat Genotypes

by Kahleen Hickey, Magnus Wood, Tom Sexton, Yunus Sahin, Taras Nazarov, Jessica Fisher, Karen A. Sanguinet, Asaph Cousins, Helmut Kirchhoff and Andrei Smertenko

Cells 2022, 11(11), 1765; https://doi.org/10.3390/cells11111765 - 27 May 2022

Cited by 17 | Viewed by 4307

Abstract

Drought resiliency strategies combine developmental, physiological, cellular, and molecular mechanisms. Here, we compare drought responses in two resilient spring wheat (Triticum aestivum) genotypes: a well-studied drought-resilient Drysdale and a resilient genotype from the US Pacific North-West Hollis. While both genotypes utilize higher [...] Read more.

Drought resiliency strategies combine developmental, physiological, cellular, and molecular mechanisms. Here, we compare drought responses in two resilient spring wheat (Triticum aestivum) genotypes: a well-studied drought-resilient Drysdale and a resilient genotype from the US Pacific North-West Hollis. While both genotypes utilize higher water use efficiency through the reduction of stomatal conductance, other mechanisms differ. First, Hollis deploys the drought escape mechanism to a greater extent than Drysdale by accelerating the flowering time and reducing root growth. Second, Drysdale uses physiological mechanisms such as non-photochemical quenching (NPQ) to dissipate the excess of harvested light energy and sustain higher F_v/F_m and ϕ_PSII, whereas Hollis maintains constant NPQ but lower F_v/F_m and ϕ_PSII values. Furthermore, more electron donors of the electron transport chain are in the oxidized state in Hollis than in Drysdale. Third, many ROS homeostasis parameters, including peroxisome abundance, transcription of peroxisome biogenesis genes PEX11 and CAT, catalase protein level, and enzymatic activity, are higher in Hollis than in Drysdale. Fourth, transcription of autophagy flux marker ATG8.4 is upregulated to a greater degree in Hollis than in Drysdale under drought, whereas relative ATG8 protein abundance under drought stress is lower in Hollis than in Drysdale. These data demonstrate the activation of autophagy in both genotypes and a greater autophagic flux in Hollis. In conclusion, wheat varieties utilize different drought tolerance mechanisms. Combining these mechanisms within one genotype offers a promising strategy to advance crop resiliency. Full article

(This article belongs to the Special Issue Drought and Heat Stress Signalling Responses in Plants)

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16 pages, 2836 KB

Open AccessEditor’s ChoiceReview

Yeast Chronological Lifespan: Longevity Regulatory Genes and Mechanisms

by Mario G. Mirisola and Valter D. Longo

Cells 2022, 11(10), 1714; https://doi.org/10.3390/cells11101714 - 23 May 2022

Cited by 25 | Viewed by 8121

Abstract

S. cerevisiae plays a pivotal role as a model system in understanding the biochemistry and molecular biology of mammals including humans. A considerable portion of our knowledge on the genes and pathways involved in cellular growth, resistance to toxic agents, and death has [...] Read more.

S. cerevisiae plays a pivotal role as a model system in understanding the biochemistry and molecular biology of mammals including humans. A considerable portion of our knowledge on the genes and pathways involved in cellular growth, resistance to toxic agents, and death has in fact been generated using this model organism. The yeast chronological lifespan (CLS) is a paradigm to study age-dependent damage and longevity. In combination with powerful genetic screening and high throughput technologies, the CLS has allowed the identification of longevity genes and pathways but has also introduced a unicellular “test tube” model system to identify and study macromolecular and cellular damage leading to diseases. In addition, it has played an important role in studying the nutrients and dietary regimens capable of affecting stress resistance and longevity and allowing the characterization of aging regulatory networks. The parallel description of the pro-aging roles of homologs of RAS, S6 kinase, adenylate cyclase, and Tor in yeast and in higher eukaryotes in S. cerevisiae chronological survival studies is valuable to understand human aging and disease. Here we review work on the S. cerevisiae chronological lifespan with a focus on the genes regulating age-dependent macromolecular damage and longevity extension. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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9 pages, 795 KB

Open AccessEditor’s ChoiceReview

Unveiling the Function of the Mitochondrial Filament-Forming Protein LACTB in Lipid Metabolism and Cancer

by Annunziata Cascone, Maciej Lalowski, Dan Lindholm and Ove Eriksson

Cells 2022, 11(10), 1703; https://doi.org/10.3390/cells11101703 - 20 May 2022

Cited by 10 | Viewed by 3911

Abstract

LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to [...] Read more.

LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to LACTB have been published, but the exact biochemical and cell biological function of LACTB still remain elusive. In this review, we summarise the current knowledge about LACTB with particular attention to the implications of the recently published study on the cryo-electron microscopy structure of the filamentous form of LACTB. From this and other studies, several specific properties of LACTB emerge, suggesting that the protein has distinct functions in different physiological settings. Resolving these issues by further research may ultimately lead to a unified model of LACTB’s function in cell and organismal physiology. LACTB is the only member of its protein family in higher animals and LACTB may, therefore, be of particular interest for future drug targeting initiatives. Full article

(This article belongs to the Special Issue 10th Anniversary of Cells—Advances in Organelle Function)

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29 pages, 1665 KB

Open AccessEditor’s ChoiceReview

Pathogenic T-Cell Responses in Immune-Mediated Glomerulonephritis

by Alexandra Linke, Gisa Tiegs and Katrin Neumann

Cells 2022, 11(10), 1625; https://doi.org/10.3390/cells11101625 - 12 May 2022

Cited by 33 | Viewed by 9823

Abstract

Glomerulonephritis (GN) comprises a group of immune-mediated kidney diseases affecting glomeruli and the tubulointerstitium. Glomerular crescent formation is a histopathological characteristic of severe forms of GN, also referred to as crescentic GN (cGN). Based on histological findings, cGN includes anti-neutrophil cytoplasmic antibody (ANCA)-associated [...] Read more.

Glomerulonephritis (GN) comprises a group of immune-mediated kidney diseases affecting glomeruli and the tubulointerstitium. Glomerular crescent formation is a histopathological characteristic of severe forms of GN, also referred to as crescentic GN (cGN). Based on histological findings, cGN includes anti-neutrophil cytoplasmic antibody (ANCA)-associated GN, a severe form of ANCA-associated vasculitis, lupus nephritis associated with systemic lupus erythematosus, Goodpasture’s disease, and IgA nephropathy. The immunopathogenesis of cGN is associated with activation of CD4⁺ and CD8⁺ T cells, which particularly accumulate in the periglomerular and tubulointerstitial space but also infiltrate glomeruli. Clinical observations and functional studies in pre-clinical animal models provide evidence for a pathogenic role of Th1 and Th17 cell-mediated immune responses in cGN. Emerging evidence further argues that CD8⁺ T cells have a role in disease pathology and the mechanisms of activation and function of recently identified tissue-resident CD4⁺ and CD8⁺ T cells in cGN are currently under investigation. This review summarizes the mechanisms of pathogenic T-cell responses leading to glomerular damage and renal inflammation in cGN. Advanced knowledge of the underlying immune mechanisms involved with cGN will enable the identification of novel therapeutic targets for the replacement or reduction in standard immunosuppressive therapy or the treatment of refractory disease. Full article

(This article belongs to the Special Issue Immune Mechanisms in Glomerulonephritis)

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20 pages, 1732 KB

Open AccessEditor’s ChoiceReview

Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis

by I-Chen Chen, Yi-Ching Liu, Yen-Hsien Wu, Shih-Hsing Lo, Zen-Kong Dai, Jong-Hau Hsu and Yu-Hsin Tseng

Cells 2022, 11(9), 1543; https://doi.org/10.3390/cells11091543 - 4 May 2022

Cited by 10 | Viewed by 4547

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, and it has a worse prognosis than non-small cell lung cancer. The pathomechanism of IPF is not fully understood, but it has been suggested that repeated microinjuries of epithelial cells [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, and it has a worse prognosis than non-small cell lung cancer. The pathomechanism of IPF is not fully understood, but it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts. These activated myofibroblasts express α smooth muscle actin and release extracellular matrix to promote matrix deposition and tissue remodeling. Under physiological conditions, the remodeling process stops once wound healing is complete. However, in the lungs of IPF patients, myofibroblasts re-main active and deposit excess extracellular matrix. This leads to the destruction of alveolar tissue, the loss of lung elastic recoil, and a rapid decrease in lung function. Some evidence has indicated that proteasomal inhibition combats fibrosis by inhibiting the expressions of extracellular matrix proteins and metalloproteinases. However, the mechanisms by which proteasome inhibitors may protect against fibrosis are not known. This review summarizes the current research on proteasome inhibitors for pulmonary fibrosis, and provides a reference for whether proteasome inhibitors have the potential to become new drugs for the treatment of pulmonary fibrosis. Full article

(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms of Cardiovascular and Pulmonary Diseases)

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14 pages, 2870 KB

Open AccessEditor’s ChoiceArticle

Focused Ultrasound Treatment of a Spheroid In Vitro Tumour Model

by Lisa Landgraf, Adam Kozlowski, Xinrui Zhang, Marc Fournelle, Franz-Josef Becker, Steffen Tretbar and Andreas Melzer

Cells 2022, 11(9), 1518; https://doi.org/10.3390/cells11091518 - 30 Apr 2022

Cited by 20 | Viewed by 4052

Abstract

Focused ultrasound (FUS) is a non-invasive technique producing a variety of biological effects by either thermal or mechanical mechanisms of ultrasound interaction with the targeted tissue. FUS could bring benefits, e.g., tumour sensitisation, immune stimulation, and targeted drug delivery, but investigation of FUS [...] Read more.

Focused ultrasound (FUS) is a non-invasive technique producing a variety of biological effects by either thermal or mechanical mechanisms of ultrasound interaction with the targeted tissue. FUS could bring benefits, e.g., tumour sensitisation, immune stimulation, and targeted drug delivery, but investigation of FUS effects at the cellular level is still missing. New techniques are commonly tested in vitro on two-dimensional (2D) monolayer cancer cell culture models. The 3D tumour model—spheroid—is mainly utilised to mimic solid tumours from an architectural standpoint. It is a promising method to simulate the characteristics of tumours in vitro and their various responses to therapeutic alternatives. This study aimed to evaluate the effects of FUS on human prostate and glioblastoma cancer tumour spheroids in vitro. The experimental follow-up enclosed the measurements of spheroid integrity and growth kinetics, DNA damage, and cellular metabolic activity by measuring intracellular ATP content in the spheroids. Our results showed that pulsed FUS treatment induced molecular effects in 3D tumour models. With the disruption of the spheroid integrity, we observed an increase in DNA double-strand breaks, leading to damage in the cancer cells depending on the cancer cell type. Full article

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17 pages, 4131 KB

Open AccessEditor’s ChoiceArticle

Sarco/Endoplasmic Reticulum Ca²⁺ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice

by Toyokazu Kimura, Kazuki Kagami, Atsushi Sato, Ayumu Osaki, Kei Ito, Shunpei Horii, Takumi Toya, Nobuyuki Masaki, Risako Yasuda, Yuji Nagatomo and Takeshi Adachi

Cells 2022, 11(9), 1488; https://doi.org/10.3390/cells11091488 - 28 Apr 2022

Cited by 11 | Viewed by 3681

Abstract

Background: Sarco/endoplasmic reticulum Ca²⁺-ATPase2 (SERCA2) is impaired in various organs in animal models of diabetes. The purpose of this study was to test the effects of an allosteric SERCA2 activator (CDN1163) on glucose intolerance, hepatosteatosis, skeletal muscle function, and endothelial dysfunction [...] Read more.

Background: Sarco/endoplasmic reticulum Ca²⁺-ATPase2 (SERCA2) is impaired in various organs in animal models of diabetes. The purpose of this study was to test the effects of an allosteric SERCA2 activator (CDN1163) on glucose intolerance, hepatosteatosis, skeletal muscle function, and endothelial dysfunction in diabetic (db/db) mice. Methods: Either CDN1163 or vehicle was injected intraperitoneally into 16-week-old male control and db/db mice for 5 consecutive days. Results: SERCA2 protein expression was decreased in the aorta of db/db mice. In isometric tension measurements of aortic rings from db/db mice treated with CDN1163, acetylcholine (ACh)-induced relaxation was improved. In vivo intraperitoneal administrations of CDN 1163 also increased ACh-induced relaxation. Moreover, CDN1163 significantly decreased blood glucose in db/db mice at 60 and 120 min during a glucose tolerance test; it also decreased serum insulin levels, hepatosteatosis, and oxygen consumption in skeletal muscle during the early period of exercise in db/db mice. Conclusions: CDN1163 directly improved aortic endothelial dysfunction in db/db mice. Moreover, CDN1163 improved hepatosteatosis, skeletal muscle function, and insulin resistance in db/db mice. The activation of SERCA2 might be a strategy for the all the tissue expressed SERCA2a improvement of endothelial dysfunction and the target for the organs related to insulin resistance. Full article

(This article belongs to the Section Cellular Metabolism)

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22 pages, 1552 KB

Open AccessEditor’s ChoiceReview

Interaction of Neural Stem Cells (NSCs) and Mesenchymal Stem Cells (MSCs) as a Promising Approach in Brain Study and Nerve Regeneration

by Agnieszka Kaminska, Klaudia Radoszkiewicz, Paulina Rybkowska, Aleksandra Wedzinska and Anna Sarnowska

Cells 2022, 11(9), 1464; https://doi.org/10.3390/cells11091464 - 26 Apr 2022

Cited by 53 | Viewed by 8840

Abstract

Rapid developments in stem cell research in recent years have provided a solid foundation for their use in medicine. Over the last few years, hundreds of clinical trials have been initiated in a wide panel of indications. Disorders and injuries of the nervous [...] Read more.

Rapid developments in stem cell research in recent years have provided a solid foundation for their use in medicine. Over the last few years, hundreds of clinical trials have been initiated in a wide panel of indications. Disorders and injuries of the nervous system still remain a challenge for the regenerative medicine. Neural stem cells (NSCs) are the optimal cells for the central nervous system restoration as they can differentiate into mature cells and, most importantly, functional neurons and glial cells. However, their application is limited by multiple factors such as difficult access to source material, limited cells number, problematic, long and expensive cultivation in vitro, and ethical considerations. On the other hand, according to the available clinical databases, most of the registered clinical trials involving cell therapies were carried out with the use of mesenchymal stem/stromal/signalling cells (MSCs) obtained from afterbirth or adult human somatic tissues. MSCs are the multipotent cells which can also differentiate into neuron-like and glia-like cells under proper conditions in vitro; however, their main therapeutic effect is more associated with secretory and supportive properties. MSCs, as a natural component of cell niche, affect the environment through immunomodulation as well as through the secretion of the trophic factors. In this review, we discuss various therapeutic strategies and activated mechanisms related to bilateral MSC–NSC interactions, differentiation of MSCs towards the neural cells (subpopulation of crest-derived cells) under the environmental conditions, bioscaffolds, or co-culture with NSCs by recreating the conditions of the neural cell niche. Full article

(This article belongs to the Special Issue Neural Stem Cells: Developmental Mechanisms and Disease Modelling)

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29 pages, 7944 KB

Open AccessEditor’s ChoiceArticle

Obesity Affects the Proliferative Potential of Equine Endometrial Progenitor Cells and Modulates Their Molecular Phenotype Associated with Mitochondrial Metabolism

by Agnieszka Smieszek, Klaudia Marcinkowska, Ariadna Pielok, Mateusz Sikora, Lukas Valihrach, Elaine Carnevale and Krzysztof Marycz

Cells 2022, 11(9), 1437; https://doi.org/10.3390/cells11091437 - 24 Apr 2022

Cited by 9 | Viewed by 3808

Abstract

The study aimed to investigate the influence of obesity on cellular features of equine endometrial progenitor cells (Eca EPCs), including viability, proliferation capacity, mitochondrial metabolism, and oxidative homeostasis. Eca EPCs derived from non-obese (non-OB) and obese (OB) mares were characterized by cellular phenotype [...] Read more.

The study aimed to investigate the influence of obesity on cellular features of equine endometrial progenitor cells (Eca EPCs), including viability, proliferation capacity, mitochondrial metabolism, and oxidative homeostasis. Eca EPCs derived from non-obese (non-OB) and obese (OB) mares were characterized by cellular phenotype and multipotency. Obesity-induced changes in the activity of Eca EPCs include the decline of their proliferative activity, clonogenic potential, mitochondrial metabolism, and enhanced oxidative stress. Eca EPCs isolated from obese mares were characterized by an increased occurrence of early apoptosis, loss of mitochondrial dynamics, and senescence-associated phenotype. Attenuated metabolism of Eca EPCs OB was related to increased expression of pro-apoptotic markers (CASP9, BAX, P53, P21), enhanced expression of OPN, PI3K, and AKT, simultaneously with decreased signaling stabilizing cellular homeostasis (including mitofusin, SIRT1, FOXP3). Obesity alters functional features and the self-renewal potential of endometrial progenitor cells. The impaired cytophysiology of progenitor cells from obese endometrium predicts lower regenerative capacity if used as autologous transplants. Full article

(This article belongs to the Special Issue Cellular and Clinical Mechanisms of Obesity and Its Complications)

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20 pages, 2737 KB

Open AccessEditor’s ChoiceArticle

Cannabinoids Alleviate the LPS-Induced Cytokine Storm via Attenuating NLRP3 Inflammasome Signaling and TYK2-Mediated STAT3 Signaling Pathways In Vitro

by Santosh V. Suryavanshi, Mariia Zaiachuk, Nazar Pryimak, Igor Kovalchuk and Olga Kovalchuk

Cells 2022, 11(9), 1391; https://doi.org/10.3390/cells11091391 - 20 Apr 2022

Cited by 52 | Viewed by 6897

Abstract

Cannabinoids, mainly cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), are the most studied group of compounds obtained from Cannabis sativa because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic [...] Read more.

Cannabinoids, mainly cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), are the most studied group of compounds obtained from Cannabis sativa because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic inflammatory diseases; however, the mechanisms remain largely unclear. Cytokine storm, a dysregulated severe inflammatory response by our immune system, is involved in the pathogenesis of numerous chronic inflammatory disorders, including coronavirus disease 2019 (COVID-19), which results in the accumulation of pro-inflammatory cytokines. Therefore, we hypothesized that CBD and THC reduce the levels of pro-inflammatory cytokines by inhibiting key inflammatory signaling pathways. The nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling has been implicated in a variety of chronic inflammatory diseases, which results in the release of pyroptotic cytokines, interleukin-1β (IL-1β) and IL-18. Likewise, the activation of the signal transducer and activator of transcription-3 (STAT3) causes increased expression of pro-inflammatory cytokines. We studied the effects of CBD and THC on lipopolysaccharide (LPS)-induced inflammatory response in human THP-1 macrophages and primary human bronchial epithelial cells (HBECs). Our results revealed that CBD and, for the first time, THC significantly inhibited NLRP3 inflammasome activation following LPS + ATP stimulation, leading to a reduction in the levels of IL-1β in THP-1 macrophages and HBECs. CBD attenuated the phosphorylation of nuclear factor-κB (NF-κB), and both cannabinoids inhibited the generation of oxidative stress post-LPS. Our multiplex ELISA data revealed that CBD and THC significantly diminished the levels of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) after LPS treatment in THP-1 macrophages and HBECs. In addition, the phosphorylation of STAT3 was significantly downregulated by CBD and THC in THP-1 macrophages and HBECs, which was in turn attributed to the reduced phosphorylation of tyrosine kinase-2 (TYK2) by CBD and THC after LPS stimulation in these cells. Overall, CBD and THC were found to be effective in alleviating the LPS-induced cytokine storm in human macrophages and primary HBECs, at least via modulation of NLRP3 inflammasome and STAT3 signaling pathways. The encouraging results from this study warrant further investigation of these cannabinoids in vivo. Full article

(This article belongs to the Collection Novel Insights into Cannabinoid Receptors, Molecular Targets, and Therapeutic Potentials)

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18 pages, 2166 KB

Open AccessEditor’s ChoiceArticle

NFAT Factors Are Dispensable for the Development but Are Critical for the Maintenance of Foxp3⁺ Regulatory T Cells

by Carlotta Barahona de Brito and Amiya Kumar Patra

Cells 2022, 11(9), 1397; https://doi.org/10.3390/cells11091397 - 20 Apr 2022

Cited by 2 | Viewed by 2796

Abstract

The transcription factors of the nuclear factor of activated T cell (NFAT) family play a crucial role in multiple aspects of T cell function. It has recently been reported that NFATs play an important role in the suppressive function of CD4⁺CD25 [...] Read more.

The transcription factors of the nuclear factor of activated T cell (NFAT) family play a crucial role in multiple aspects of T cell function. It has recently been reported that NFATs play an important role in the suppressive function of CD4⁺CD25⁺Foxp3⁺ regulatory T (T_reg) cells. In this study, we have investigated the role of NFATs in the thymic development of T_reg cells in mice. We show that NFAT factors are dispensable for the development of Foxp3⁺ T_reg cells in the thymus but are critical for the maintenance of both the phenotype and survival of T_reg cells in the thymus as well as in peripheral lymphoid organs. Specifically, the homeostasis of CD4⁺CD25⁺Foxp3⁺ but not the CD4⁺CD25⁻Foxp3⁺ fraction is severely perturbed when NFAT signaling is blocked, leading to a strongly reduced T_reg population. We underscored this intriguing effect of NFAT on CD4⁺CD25⁺Foxp3⁺ T_reg cells to the disruption of survival signals provided by interleukin 2 (IL-2). Accordingly, blocking T_reg cell death by abolishing the activity of pro-apoptotic Bcl-2 family member Bim, compensated for the survival defects induced due to a lack of NFAT-IL-2-IL-2R signaling. Inhibition of NFAT activity led to a strong reduction in the number of Foxp3⁺ T_reg cells; however, it did not influence the level of Foxp3 expression on an individual cell basis. In addition, we show a differential effect of IL-2 and IL-7 signaling on Foxp3⁺ T_reg versus CD4⁺CD25⁻ T cell development, again underlining the dispensability of NFAT signaling in the development, but not in the maintenance of Foxp3⁺ T_reg cells. Full article

(This article belongs to the Section Cellular Immunology)

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18 pages, 1180 KB

Open AccessEditor’s ChoiceReview

Key Signaling in Alcohol-Associated Liver Disease: The Role of Bile Acids

by Grayson W. Way, Kaitlyn G. Jackson, Shreya R. Muscu and Huiping Zhou

Cells 2022, 11(8), 1374; https://doi.org/10.3390/cells11081374 - 18 Apr 2022

Cited by 26 | Viewed by 45140

Abstract

Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead [...] Read more.

Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD). In this review, we summarize the recent advances in the understanding of the mechanisms by which alcohol consumption induces hepatic injury and the role of BA-mediated signaling in the pathogenesis of ALD. Full article

(This article belongs to the Special Issue New Aspects and Mechanisms in Liver Diseases)

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42 pages, 1307 KB

Open AccessEditor’s ChoiceReview

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

by Angelica Varesi, Adelaide Carrara, Vitor Gomes Pires, Valentina Floris, Elisa Pierella, Gabriele Savioli, Sakshi Prasad, Ciro Esposito, Giovanni Ricevuti, Salvatore Chirumbolo and Alessia Pascale

Cells 2022, 11(8), 1367; https://doi.org/10.3390/cells11081367 - 17 Apr 2022

Cited by 86 | Viewed by 15650

Abstract

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, [...] Read more.

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ_1–42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease. Full article

(This article belongs to the Special Issue Biomarkers of Alzheimer’s Disease: New Insights)

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21 pages, 4959 KB

Open AccessEditor’s ChoiceArticle

Human iPSC-Derived Renal Cells Change Their Immunogenic Properties during Maturation: Implications for Regenerative Therapies

by Bella Rossbach, Krithika Hariharan, Nancy Mah, Su-Jun Oh, Hans-Dieter Volk, Petra Reinke and Andreas Kurtz

Cells 2022, 11(8), 1328; https://doi.org/10.3390/cells11081328 - 13 Apr 2022

Cited by 7 | Viewed by 3473

Abstract

The success of human induced pluripotent stem cell (hiPSC)-based therapy critically depends on understanding and controlling the immunological effects of the hiPSC-derived transplant. While hiPSC-derived cells used for cell therapy are often immature with post-grafting maturation, immunological properties may change, with adverse effects [...] Read more.

The success of human induced pluripotent stem cell (hiPSC)-based therapy critically depends on understanding and controlling the immunological effects of the hiPSC-derived transplant. While hiPSC-derived cells used for cell therapy are often immature with post-grafting maturation, immunological properties may change, with adverse effects on graft tolerance and control. In the present study, the allogeneic and autologous cellular immunity of hiPSC-derived progenitor and terminally differentiated cells were investigated in vitro. In contrast to allogeneic primary cells, hiPSC-derived early renal progenitors and mature renal epithelial cells are both tolerated not only by autologous but also by allogeneic T cells. These immune-privileged properties result from active immunomodulation and low immune visibility, which decrease during the process of cell maturation. However, autologous and allogeneic natural killer (NK) cell responses are not suppressed by hiPSC-derived renal cells and effectively change NK cell activation status. These findings clearly show a dynamic stage-specific dependency of autologous and allogeneic T and NK cell responses, with consequences for effective cell therapies. The study suggests that hiPSC-derived early progenitors may provide advantageous immune-suppressive properties when applied in cell therapy. The data furthermore indicate a need to suppress NK cell activation in allogeneic as well as autologous settings. Full article

(This article belongs to the Special Issue Stem Cells in Personalized Medicine 2021)

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