Cells

27 pages, 3449 KiB

Open AccessEditor’s ChoiceReview

Mesenchymal Stem Cell-Derived Extracellular Vesicles for Therapeutic Use and in Bioengineering Applications

by Caroline McLaughlin, Pallab Datta, Yogendra P. Singh, Alexis Lo, Summer Horchler, Irina A. Elcheva, Ibrahim T. Ozbolat, Dino J. Ravnic and Srinivas V. Koduru

Cells 2022, 11(21), 3366; https://doi.org/10.3390/cells11213366 - 25 Oct 2022

Cited by 25 | Viewed by 5175

Abstract

Extracellular vesicles (EVs) are small lipid bilayer-delimited particles that are naturally released from cells into body fluids, and therefore can travel and convey regulatory functions in the distal parts of the body. EVs can transmit paracrine signaling by carrying over cytokines, chemokines, growth [...] Read more.

Extracellular vesicles (EVs) are small lipid bilayer-delimited particles that are naturally released from cells into body fluids, and therefore can travel and convey regulatory functions in the distal parts of the body. EVs can transmit paracrine signaling by carrying over cytokines, chemokines, growth factors, interleukins (ILs), transcription factors, and nucleic acids such as DNA, mRNAs, microRNAs, piRNAs, lncRNAs, sn/snoRNAs, mtRNAs and circRNAs; these EVs travel to predecided destinations to perform their functions. While mesenchymal stem cells (MSCs) have been shown to improve healing and facilitate treatments of various diseases, the allogenic use of these cells is often accompanied by serious adverse effects after transplantation. MSC-produced EVs are less immunogenic and can serve as an alternative to cellular therapies by transmitting signaling or delivering biomaterials to diseased areas of the body. This review article is focused on understanding the properties of EVs derived from different types of MSCs and MSC–EV-based therapeutic options. The potential of modern technologies such as 3D bioprinting to advance EV-based therapies is also discussed. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles)

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11 pages, 625 KiB

Open AccessEditor’s ChoiceReview

Morbidity and Mortality of Neutropenic Patients in Visceral Surgery: A Narrative Review

by Ann-Kathrin Lederer, Fabian Bartsch, Markus Moehler, Peter Gaßmann and Hauke Lang

Cells 2022, 11(20), 3314; https://doi.org/10.3390/cells11203314 - 21 Oct 2022

Cited by 4 | Viewed by 3145

Abstract

Leukocytes are essential for the function of the immune system and cell–cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are [...] Read more.

Leukocytes are essential for the function of the immune system and cell–cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are neutrophilic granulocytes, and leukopenia is, therefore, mostly characterized by a decrease in neutrophilic granulocytes. The consequence of neutropenia is increased susceptibility to infection, but also healing disorders are suggestable due to the disturbed cell–cell interaction. While there is no surgical treatment for leucocyte disorders, patients suffering from neutropenia are sometimes in need of surgery for other reasons. Less is known about the morbidity and mortality of this patients, which is why this narrative review critically summarizes the results of recent research in this particular field. The results of this review suggest that neutropenic patients in need of emergency surgery have a higher mortality risk compared to non-neutropenic patients. In contrast, in elective surgery, there was not a clear tendency for a higher mortality risk of neutropenic patients. The role of neutrophilic granulocytes in inflammation and immunity in surgical patients is emphasized by the results, but most of the evaluated studies showed methodological flaws due to small sample sizes or risk of bias. Further research has to evaluate the risk for postoperative complications, particularly of infectious complications such as surgical site infections, in neutropenic patients undergoing elective surgery, and should address the role of neutrophilic function in postoperative morbidity and mortality. Full article

(This article belongs to the Collection Emerging Roles of Neutrophil in Inflammation and Immunity)

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27 pages, 7126 KiB

Open AccessEditor’s ChoiceArticle

Dendritic Cells or Macrophages? The Microenvironment of Human Clear Cell Renal Cell Carcinoma Imprints a Mosaic Myeloid Subtype Associated with Patient Survival

by Dorothee Brech, Anna S. Herbstritt, Sarah Diederich, Tobias Straub, Evangelos Kokolakis, Martin Irmler, Johannes Beckers, Florian A. Büttner, Elke Schaeffeler, Stefan Winter, Matthias Schwab, Peter J. Nelson and Elfriede Noessner

Cells 2022, 11(20), 3289; https://doi.org/10.3390/cells11203289 - 19 Oct 2022

Cited by 9 | Viewed by 4514

Abstract

Since their initial description by Elie Metchnikoff, phagocytes have sparked interest in a variety of biologic disciplines. These important cells perform central functions in tissue repair and immune activation as well as tolerance. Myeloid cells can be immunoinhibitory, particularly in the tumor microenvironment, [...] Read more.

Since their initial description by Elie Metchnikoff, phagocytes have sparked interest in a variety of biologic disciplines. These important cells perform central functions in tissue repair and immune activation as well as tolerance. Myeloid cells can be immunoinhibitory, particularly in the tumor microenvironment, where their presence is generally associated with poor patient prognosis. These cells are highly adaptable and plastic, and can be modulated to perform desired functions such as antitumor activity, if key programming molecules can be identified. Human clear cell renal cell carcinoma (ccRCC) is considered immunogenic; yet checkpoint blockades that target T cell dysfunction have shown limited clinical efficacy, suggesting additional layers of immunoinhibition. We previously described “enriched-in-renal cell carcinoma” (erc) DCs that were often found in tight contact with dysfunctional T cells. Using transcriptional profiling and flow cytometry, we describe here that ercDCs represent a mosaic cell type within the macrophage continuum co-expressing M1 and M2 markers. The polarization state reflects tissue-specific signals that are characteristic of RCC and renal tissue homeostasis. ErcDCs are tissue-resident with increasing prevalence related to tumor grade. Accordingly, a high ercDC score predicted poor patient survival. Within the profile, therapeutic targets (VSIG4, NRP1, GPNMB) were identified with promise to improve immunotherapy. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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27 pages, 893 KiB

Open AccessEditor’s ChoiceReview

The Extracellular Matrix and Neuroblastoma Cell Communication—A Complex Interplay and Its Therapeutic Implications

by Irena Horwacik

Cells 2022, 11(19), 3172; https://doi.org/10.3390/cells11193172 - 10 Oct 2022

Cited by 12 | Viewed by 3741

Abstract

Neuroblastoma (NB) is a pediatric neuroendocrine neoplasm. It arises from the sympatho-adrenal lineage of neural-crest-derived multipotent progenitor cells that fail to differentiate. NB is the most common extracranial tumor in children, and it manifests undisputed heterogeneity. Unsatisfactory outcomes of high-risk (HR) NB patients [...] Read more.

Neuroblastoma (NB) is a pediatric neuroendocrine neoplasm. It arises from the sympatho-adrenal lineage of neural-crest-derived multipotent progenitor cells that fail to differentiate. NB is the most common extracranial tumor in children, and it manifests undisputed heterogeneity. Unsatisfactory outcomes of high-risk (HR) NB patients call for more research to further inter-relate treatment and molecular features of the disease. In this regard, it is well established that in the tumor microenvironment (TME), malignant cells are engaged in complex and dynamic interactions with the extracellular matrix (ECM) and stromal cells. The ECM can be a source of both pro- and anti-tumorigenic factors to regulate tumor cell fate, such as survival, proliferation, and resistance to therapy. Moreover, the ECM composition, organization, and resulting signaling networks are vastly remodeled during tumor progression and metastasis. This review mainly focuses on the molecular mechanisms and effects of interactions of selected ECM components with their receptors on neuroblastoma cells. Additionally, it describes roles of enzymes modifying and degrading ECM in NB. Finally, the article gives examples on how the knowledge is exploited for prognosis and to yield new treatment options for NB patients. Full article

(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy)

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10 pages, 935 KiB

Open AccessEditor’s ChoiceHypothesis

AIRE in Male Fertility: A New Hypothesis

by Jana Petrusová, Jasper Manning and Dominik Filipp

Cells 2022, 11(19), 3168; https://doi.org/10.3390/cells11193168 - 9 Oct 2022

Cited by 1 | Viewed by 2230

Abstract

Male infertility affects approximately 14% of all European men, of which ~44% are characterized as idiopathic. There is an urgency to identify the factors that affect male fertility. One such factor, Autoimmune Regulator (AIRE), a protein found in the thymus, has been studied [...] Read more.

Male infertility affects approximately 14% of all European men, of which ~44% are characterized as idiopathic. There is an urgency to identify the factors that affect male fertility. One such factor, Autoimmune Regulator (AIRE), a protein found in the thymus, has been studied in the context of central tolerance functioning as a nuclear transcription modulator, responsible for the expression of tissue-restricted antigens in specialized thymic cells that prevent autoimmunity. While its expression in the testes remains enigmatic, we recently observed that sterility in mice correlates with the absence of Aire in the testes, regardless of the deficient expression in medullary thymic epithelial cells or cells of the hematopoietic system. By assessing the Aire transcript levels, we discovered that Sertoli cells are the exclusive source of Aire in the testes, where it most likely plays a non-immune role, suggesting an unknown mechanism by which testicular Aire regulates fertility. Here, we discuss these results in the context of previous reports which have suggested that infertility observed in Aire deficient mice is of an autoimmune aetiology. We present an alternative point of view for the role of Aire in testes in respect to fertility altering the perspective of how Aire’s function in the testes is currently perceived. Full article

(This article belongs to the Section Reproductive Cells and Development)

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11 pages, 1632 KiB

Open AccessEditor’s ChoiceArticle

Characterization of the Aquaporin-9 Inhibitor RG100204 In Vitro and in db/db Mice

by Marilina Florio, Angelica Engfors, Patrizia Gena, Jessica Larsson, Alessandro Massaro, Stella Timpka, Martina Kvist Reimer, Per Kjellbom, Eric Beitz, Urban Johanson, Michael Rützler and Giuseppe Calamita

Cells 2022, 11(19), 3118; https://doi.org/10.3390/cells11193118 - 4 Oct 2022

Cited by 8 | Viewed by 2747

Abstract

Aquaporin-9 (AQP9) is a facilitator of glycerol and other small neutral solute transmembrane diffusion. Identification of specific inhibitors for aquaporin family proteins has been difficult, due to high sequence similarity between the 13 human isoforms, and due to the limited channel surface areas [...] Read more.

Aquaporin-9 (AQP9) is a facilitator of glycerol and other small neutral solute transmembrane diffusion. Identification of specific inhibitors for aquaporin family proteins has been difficult, due to high sequence similarity between the 13 human isoforms, and due to the limited channel surface areas that permit inhibitor binding. The few AQP9 inhibitor molecules described to date were not suitable for in vivo experiments. We now describe the characterization of a new small molecule AQP9 inhibitor, RG100204 in cell-based calcein-quenching assays, and by stopped-flow light-scattering recordings of AQP9 permeability in proteoliposomes. Moreover, we investigated the effects of RG100204 on glycerol metabolism in mice. In cell-based assays, RG100204 blocked AQP9 water permeability and glycerol permeability with similar, high potency (~5 × 10⁻⁸ M). AQP9 channel blocking by RG100204 was confirmed in proteoliposomes. After oral gavage of db/db mice with RG100204, a dose-dependent elevation of plasma glycerol was observed. A blood glucose-lowering effect was not statistically significant. These experiments establish RG100204 as a direct blocker of the AQP9 channel, and suggest its use as an experimental tool for in vivo experiments on AQP9 function. Full article

(This article belongs to the Section Cellular Metabolism)

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17 pages, 5246 KiB

Open AccessEditor’s ChoiceArticle

Proteomic and Phosphoproteomic Profiling Reveals the Oncogenic Role of Protein Kinase D Family Kinases in Cholangiocarcinoma

by Yun Lu, Xiangyu Li, Kai Zhao, Yuanxin Shi, Zhengdong Deng, Wei Yao and Jianming Wang

Cells 2022, 11(19), 3088; https://doi.org/10.3390/cells11193088 - 30 Sep 2022

Cited by 6 | Viewed by 2998

Abstract

Cholangiocarcinoma (CCA) is a lethal malignancy in the hepatobiliary system, with dysregulated protein expression and phosphorylation signaling. However, the protein and phosphorylation signatures of CCAs are little-known. Here, we performed the proteomic and phosphoproteomic profiling of tumors and normal adjacent tissues (NATs) from [...] Read more.

Cholangiocarcinoma (CCA) is a lethal malignancy in the hepatobiliary system, with dysregulated protein expression and phosphorylation signaling. However, the protein and phosphorylation signatures of CCAs are little-known. Here, we performed the proteomic and phosphoproteomic profiling of tumors and normal adjacent tissues (NATs) from patients with CCA and predicted eleven PKs high-potentially related to CCA with a comprehensive inference of the functional protein kinases (PKs) (CifPK) pipeline. Besides the two known CCA-associated PKs, we screened the remaining candidates and uncovered five PKs as novel regulators in CCA. Specifically, the protein kinase D (PKD) family members, including PRKD1, PRKD2, and PRKD3, were identified as critical regulators in CCA. Moreover, the pan-inhibitor of the PKD family, 1-naphthyl PP1 (1-NA-PP1), was validated as a potent agent for inhibiting the proliferation, migration, and invasion ability of CCA cells. This study reveals new PKs associated with CCA and suggests PRKD kinases as novel treatment targets for CCA. Full article

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

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15 pages, 2006 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Complex Relation between Atrial Cardiomyopathy and Thrombogenesis

by Elisa D’Alessandro, Joris Winters, Frans A. van Nieuwenhoven, Ulrich Schotten and Sander Verheule

Cells 2022, 11(19), 2963; https://doi.org/10.3390/cells11192963 - 22 Sep 2022

Cited by 11 | Viewed by 2902

Abstract

Heart disease, as well as systemic metabolic alterations, can leave a ‘fingerprint’ of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy [...] Read more.

Heart disease, as well as systemic metabolic alterations, can leave a ‘fingerprint’ of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability. Full article

(This article belongs to the Special Issue Molecular Biology of Atrial Myocardium)

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14 pages, 876 KiB

Open AccessEditor’s ChoiceReview

Molecular Regulators of Embryonic Diapause and Cancer Diapause-like State

by Abdiasis M. Hussein, Nanditaa Balachandar, Julie Mathieu and Hannele Ruohola-Baker

Cells 2022, 11(19), 2929; https://doi.org/10.3390/cells11192929 - 20 Sep 2022

Cited by 16 | Viewed by 7333

Abstract

Embryonic diapause is an enigmatic state of dormancy that interrupts the normally tight connection between developmental stages and time. This reproductive strategy and state of suspended development occurs in mice, bears, roe deer, and over 130 other mammals and favors the survival of [...] Read more.

Embryonic diapause is an enigmatic state of dormancy that interrupts the normally tight connection between developmental stages and time. This reproductive strategy and state of suspended development occurs in mice, bears, roe deer, and over 130 other mammals and favors the survival of newborns. Diapause arrests the embryo at the blastocyst stage, delaying the post-implantation development of the embryo. This months-long quiescence is reversible, in contrast to senescence that occurs in aging stem cells. Recent studies have revealed critical regulators of diapause. These findings are important since defects in the diapause state can cause a lack of regeneration and control of normal growth. Controlling this state may also have therapeutic applications since recent findings suggest that radiation and chemotherapy may lead some cancer cells to a protective diapause-like, reversible state. Interestingly, recent studies have shown the metabolic regulation of epigenetic modifications and the role of microRNAs in embryonic diapause. In this review, we discuss the molecular mechanism of diapause induction. Full article

(This article belongs to the Collection Exclusive Papers from Editorial Board Members and Invited Scholars in Cells)

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20 pages, 3466 KiB

Open AccessEditor’s ChoiceArticle

Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue: In Vivo and In Vitro Studies

by Lei Wang, Lieke E. J. van Iersel, Charlotte E. Pelgrim, Jingyi Lu, Ingrid van Ark, Thea Leusink-Muis, Harry R. Gosker, Ramon C. J. Langen, Annemie M. W. J. Schols, Josep M. Argilés, Ardy van Helvoort, Aletta D. Kraneveld, Johan Garssen, Paul A. J. Henricks, Gert Folkerts and Saskia Braber

Cells 2022, 11(18), 2893; https://doi.org/10.3390/cells11182893 - 16 Sep 2022

Cited by 13 | Viewed by 5537

Abstract

Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro [...] Read more.

Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis. Full article

(This article belongs to the Special Issue Metabolic Alterations and Cellular Stress Responses in Chronic Obstructive Pulmonary Disease)

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15 pages, 3542 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Three-Dimensional Trophoblast Spheroids: An Alternative Model to Study the Physiological Properties of the Placental Unit

by Violeta Stojanovska, Susanne Arnold, Mario Bauer, Hermann Voss, Stefan Fest and Ana Claudia Zenclussen

Cells 2022, 11(18), 2884; https://doi.org/10.3390/cells11182884 - 15 Sep 2022

Cited by 16 | Viewed by 3929

Abstract

It was postulated that 3D cell culture models more accurately reflect the complex tissue physiology and morphology in comparison to 2D cell monolayers. Currently, there is a shortage of well-characterized and easily maintainable high-throughput experimental models of the human placenta. Here, we characterized [...] Read more.

It was postulated that 3D cell culture models more accurately reflect the complex tissue physiology and morphology in comparison to 2D cell monolayers. Currently, there is a shortage of well-characterized and easily maintainable high-throughput experimental models of the human placenta. Here, we characterized three different 3D cultures (e.g., spheroids) derived from trophoblast cell lines and studied their functionality in comparison to primary fetal trophoblasts and placental tissue. The spheroid growth rates of JEG3, BeWo and HTR8/SVneo cell lines were similar among each other and were significantly larger in comparison to primary trophoblast spheroids. All spheroids exhibited migratory properties and shortest distances were registered for JEG3 spheroids. Even though all spheroids displayed invasive capabilities, only the invasive features of HTR8/SVneo spheroids resulted in specific branching. This was in agreement with the invasive properties of the spheroids obtained from primary trophoblasts. Human chorionic gonadotropin production was highest in JEG3 spheroids and only increased when stimulated with cAMP and forskolin in BeWo, but not HTR8/SVneo spheroids. The gene expression analysis confirmed that 3D trophoblast cell cultures and especially HTR8/SVneo spheroids showed considerable similarities with the gene expression profile of primary placental tissue. This study offers a broad characterization of 3D trophoblast spheroids that, in turn, can help in selecting the best model depending on the scientific question that needs to be answered. Full article

(This article belongs to the Special Issue Placental Development in Health and Disease)

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23 pages, 4047 KiB

Open AccessEditor’s ChoiceArticle

The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism

by Sonia Spinelli, Lucrezia Guida, Tiziana Vigliarolo, Mario Passalacqua, Giulia Begani, Mirko Magnone, Laura Sturla, Andrea Benzi, Pietro Ameri, Edoardo Lazzarini, Claudia Bearzi, Roberto Rizzi and Elena Zocchi

Cells 2022, 11(18), 2888; https://doi.org/10.3390/cells11182888 - 15 Sep 2022

Cited by 19 | Viewed by 4222

Abstract

Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We [...] Read more.

Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO. The effect of ABA and of the silencing or overexpression of LANCL1 and LANCL2 were investigated in H9c2 rat cardiomyoblasts under normoxia or hypoxia/reoxygenation. In H9c2, hypoxia induced ABA release, and ABA stimulated NO production. ABA increased the survival of H9c2 to hypoxia, and L-NAME, an inhibitor of NO synthase (NOS), abrogated this effect. ABA also increased glucose uptake and NADPH levels and increased phosphorylation of Akt, AMPK and eNOS. Overexpression or silencing of LANCL1/2 significantly increased or decreased, respectively, transcription, expression and phosphorylation of AMPK, Akt and eNOS; transcription of NAMPT, Sirt1 and the arginine transporter. The mitochondrial proton gradient and cell vitality increased in LANCL1/2-overexpressing vs. -silenced cells after hypoxia/reoxygenation, and L-NAME abrogated this difference. These results implicate the ABA-LANCL1/2 hormone-receptor system in NO-mediated cardiomyocyte protection against hypoxia. Full article

(This article belongs to the Collection Regulation of Cell Function by AMPK and Sirtuins: From Basic Research to Disease and Aging)

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14 pages, 2204 KiB

Open AccessEditor’s ChoiceArticle

Biological Pathway-Derived TMB Robustly Predicts the Outcome of Immune Checkpoint Blockade Therapy

by Ya-Ru Miao, Chun-Jie Liu, Hui Hu, Mei Yang and An-Yuan Guo

Cells 2022, 11(18), 2802; https://doi.org/10.3390/cells11182802 - 8 Sep 2022

Cited by 7 | Viewed by 3118

Abstract

Although immune checkpoint blockade (ICB) therapies have achieved great progress, the patient response varies among cancers. In this study, we analyzed the potential genomic indicators contributing to ICB therapy response. The results showed that high tumor mutation burden (TMB) failed to predict response [...] Read more.

Although immune checkpoint blockade (ICB) therapies have achieved great progress, the patient response varies among cancers. In this study, we analyzed the potential genomic indicators contributing to ICB therapy response. The results showed that high tumor mutation burden (TMB) failed to predict response in anti-PD1 treated melanoma. SERPINB3 was the most significant response-related gene in melanoma and mutations in either SERPINB3 or PEG3 can serve as an independent risk factor in melanoma. Some recurrent mutations in CSMD3 were only in responders or non-responders, indicating their diverse impacts on patient response. Enrichment scores (ES) of gene mutations in 12 biological pathways were significantly higher in responders or non-responders. Next, the P-TMB calculated from genes in these pathways was significantly related to patient response with prediction AUC 0.74–0.82 in all collected datasets. In conclusion, our work provides new insights into the application of TMB in predicting patient response, which will benefit to immunotherapy research. Full article

(This article belongs to the Special Issue Cutting Edge in Bioinformatics of Cancer Immunotherapy)

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15 pages, 1844 KiB

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 4183

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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20 pages, 1610 KiB

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 18 | Viewed by 5049

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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17 pages, 1724 KiB

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 85 | Viewed by 11299

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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16 pages, 1852 KiB

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 12 | Viewed by 3120

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 KiB

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 25 | Viewed by 8945

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 KiB

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 4072

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 KiB

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 8 | Viewed by 3490

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 KiB

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 41 | Viewed by 7272

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 KiB

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 4234

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 KiB

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 10 | Viewed by 2588

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 KiB

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 2706

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 KiB

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 33 | Viewed by 5759

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 KiB

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 5 | Viewed by 3197

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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22 pages, 6182 KiB

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 4218

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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11 pages, 2526 KiB

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 11 | Viewed by 4367

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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20 pages, 4849 KiB

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 5 | Viewed by 4944

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 KiB

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 3373

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 KiB

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 11 | Viewed by 3942

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 KiB

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 16 | Viewed by 3885

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 KiB

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 54 | Viewed by 12449

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 KiB

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 32 | Viewed by 6829

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 KiB

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 8 | Viewed by 2741

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 KiB

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 3618

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 KiB

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 17 | Viewed by 4577

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 KiB

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 6 | Viewed by 3484

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 KiB

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 3 | Viewed by 3174

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 KiB

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 13 | Viewed by 6264

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 KiB

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 14 | Viewed by 3740

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 KiB

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 4932

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 KiB

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 5 | Viewed by 3730

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 KiB

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 111 | Viewed by 12683

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 KiB

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 47 | Viewed by 9380

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 KiB

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 25 | Viewed by 6708

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 KiB

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 10 | Viewed by 3188

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 KiB

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 35 | Viewed by 7206

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 KiB

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 2928

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 KiB

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 13 | Viewed by 3954

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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