Cells

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16 pages, 2872 KiB

Open AccessEditor’s ChoiceArticle

Prognostic Significance of TWIST1, CD24, CD44, and ALDH1 Transcript Quantification in EpCAM-Positive Circulating Tumor Cells from Early Stage Breast Cancer Patients

by Areti Strati, Michail Nikolaou, Vassilis Georgoulias and Evi S. Lianidou

Cells 2019, 8(7), 652; https://doi.org/10.3390/cells8070652 - 29 Jun 2019

Cited by 46 | Viewed by 6539

Abstract

(1) Background: The aim of the study was to evaluate the prognostic significance of EMT-associated (TWIST1) and stem-cell (SC) transcript (CD24, CD44, ALDH1) quantification in EpCAM+ circulating tumor cells (CTCs) of early breast cancer patients. (2) Methods: 100 [...] Read more.

(1) Background: The aim of the study was to evaluate the prognostic significance of EMT-associated (TWIST1) and stem-cell (SC) transcript (CD24, CD44, ALDH1) quantification in EpCAM+ circulating tumor cells (CTCs) of early breast cancer patients. (2) Methods: 100 early stage breast cancer patients and 19 healthy donors were enrolled in the study. CD24, CD44, and ALDH1 transcripts of EpCAM⁺ cells were quantified using a novel highly sensitive and specific quadraplex RT-qPCR, while TWIST1 transcripts were quantified by single RT-qPCR. All patients were followed up for more than 5 years. (3) Results: A significant positive correlation between overexpression of TWIST1 and CD24^−/low/CD44^high profile was found. Kaplan–Meier analysis revealed that the ER/PR-negative (HR-) patients and those patients with more than 3 positive lymph nodes that overexpressed TWIST1 in EpCAM⁺ cells had a significant lower DFI (log rank test; p < 0.001, p < 0.001) and OS (log rank test; p = 0.006, p < 0.001). Univariate and multivariate analysis also revealed the prognostic value of TWIST1 overexpression and CD24^−/low/CD44^high and CD24^−/low/ALDH1^high profile for both DFI and OS. (4) Conclusions: Detection of TWIST1 overexpression and stem-cell (CD24, CD44, ALDH1) transcripts in EpCAM⁺ CTCs provides prognostic information in early stage breast cancer patients. Full article

(This article belongs to the Special Issue Circulating Tumor Cells: Finding Rare Events for A Huge Knowledge of Cancer Dissemination)

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18 pages, 3066 KiB

Open AccessEditor’s ChoiceArticle

Fecal Microbiota Transplantation Controls Murine Chronic Intestinal Inflammation by Modulating Immune Cell Functions and Gut Microbiota Composition

by Claudia Burrello, Maria Rita Giuffrè, Angeli Dominique Macandog, Angelica Diaz-Basabe, Fulvia Milena Cribiù, Gianluca Lopez, Francesca Borgo, Luigi Nezi, Flavio Caprioli, Maurizio Vecchi and Federica Facciotti

Cells 2019, 8(6), 517; https://doi.org/10.3390/cells8060517 - 28 May 2019

Cited by 61 | Viewed by 8827

Abstract

Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently [...] Read more.

Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently showed that therapeutic effects of FMT during acute experimental colitis are linked to functional modulation of the mucosal immune system and of the gut microbiota composition. Here we analysed the effects of therapeutic FMT administration during chronic experimental colitis, a condition more similar to that of IBD patients, on immune-mediated mucosal inflammatory pathways. Mucus and feces from normobiotic donors were orally administered to mice with established chronic Dextran Sodium Sulphate (DSS)-induced colitis. Immunophenotypes and functions of infiltrating colonic immune cells were evaluated by cytofluorimetric analysis. Compositional differences in the intestinal microbiome were analyzed by 16S rRNA sequencing. Therapeutic FMT in mice undergoing chronic intestinal inflammation was capable to decrease colonic inflammation by modulating the expression of pro-inflammatory genes, antimicrobial peptides, and mucins. Innate and adaptive mucosal immune cells manifested a reduced pro-inflammatory profile in FMT-treated mice. Finally, restoration of a normobiotic core ecology contributed to the resolution of inflammation. Thus, FMT is capable of controlling chronic intestinal experimental colitis by inducing a concerted activation of anti-inflammatory immune pathways, mechanistically supporting the positive results of FMT treatment reported in ulcerative colitis patients. Full article

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10 pages, 2521 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Single Cell RNA Sequencing Identifies Subsets of Hepatic Stellate Cells and Myofibroblasts in Liver Fibrosis

by Oliver Krenkel, Jana Hundertmark, Thomas P. Ritz, Ralf Weiskirchen and Frank Tacke

Cells 2019, 8(5), 503; https://doi.org/10.3390/cells8050503 - 24 May 2019

Cited by 168 | Viewed by 18411

Abstract

Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, [...] Read more.

Activation of hepatic stellate cells (HSCs) and their trans-differentiation towards collagen-secreting myofibroblasts (MFB) promote liver fibrosis progression. During chronic liver disease, resting HSCs become activated by inflammatory and injury signals. However, HSCs/MFB not only produce collagen, but also secrete cytokines, participate in metabolism, and have biomechanical properties. We herein aimed to characterize the heterogeneity of these liver mesenchymal cells by single cell RNA sequencing. In vivo resting HSCs or activated MFB were isolated from C57BL6/J mice challenged by carbon tetrachloride (CCl₄) intraperitoneally for 3 weeks to induce liver fibrosis and compared to in vitro cultivated MFB. While resting HSCs formed a homogenous population characterized by high platelet derived growth factor receptor β (PDGFRβ) expression, in vivo and in vitro activated MFB split into heterogeneous populations, characterized by α-smooth muscle actin (α-SMA), collagens, or immunological markers. S100 calcium binding protein A6 (S100A6) was a universal marker of activated MFB on both the gene and protein expression level. Compared to the heterogeneity of in vivo MFB, MFB in vitro sequentially and only transiently expressed marker genes, such as chemokines, during culture activation. Taken together, our data demonstrate the heterogeneity of HSCs and MFB, indicating the existence of functionally relevant subsets in hepatic fibrosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)

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17 pages, 2189 KiB

Open AccessEditor’s ChoiceArticle

Anti-Inflammatory Effects by Pharmacological Inhibition or Knockdown of Fatty Acid Amide Hydrolase in BV2 Microglial Cells

by Mikiei Tanaka, Kazuya Yagyu, Scott Sackett and Yumin Zhang

Cells 2019, 8(5), 491; https://doi.org/10.3390/cells8050491 - 22 May 2019

Cited by 32 | Viewed by 6775

Abstract

Fatty acid amide hydrolase (FAAH) has been recognized as a therapeutic target for several neurological diseases because its inhibition can exert neuroprotective and anti-inflammatory effects by boosting the endogenous levels of N-acylethanolamines. However, previous studies have shown inconsistent results by pharmacological inhibition [...] Read more.

Fatty acid amide hydrolase (FAAH) has been recognized as a therapeutic target for several neurological diseases because its inhibition can exert neuroprotective and anti-inflammatory effects by boosting the endogenous levels of N-acylethanolamines. However, previous studies have shown inconsistent results by pharmacological inhibition and genetic deletion of FAAH in response to inflammation. In this study we used two inhibitors, PF3845 and URB597, together with siRNA knockdown to characterize further the effects of FAAH inhibition in BV2 microglial cells. Treatment with PF3845 suppressed lipopolysaccharide (LPS)-induced prostaglandin E₂ (PGE₂) production, and down-regulated cyclooxygenase-2 and microsomal PGE synthase. PF3845 reduced the expression of pro-inflammatory cytokines but had no effect on the expression of anti-inflammatory cytokines. The anti-inflammatory effects of URB597 were not as potent as those of PF3845. Knockdown of FAAH also suppressed PGE₂ production and pro-inflammatory gene expression. Interestingly, FAAH knockdown enhanced expression of anti-inflammatory molecules in both the absence and presence of LPS treatment. The anti-inflammatory effects of FAAH inhibition and knockdown were not affected by the cannabinoid receptor antagonists or the peroxisome proliferator-activated receptor (PPAR) antagonists. Although inhibition and knockdown of FAAH have potent anti-inflammatory effects and possibly lead to the dynamic change of microglial gene regulation, the underlying mechanisms remain to be elucidated. Full article

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18 pages, 19224 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

An In Vitro System for Evaluating Molecular Targeted Drugs Using Lung Patient-Derived Tumor Organoids

by Nobuhiko Takahashi, Hirotaka Hoshi, Arisa Higa, Gen Hiyama, Hirosumi Tamura, Mayu Ogawa, Kosuke Takagi, Kazuhito Goda, Naoyuki Okabe, Satoshi Muto, Hiroyuki Suzuki, Kenju Shimomura, Shinya Watanabe and Motoki Takagi

Cells 2019, 8(5), 481; https://doi.org/10.3390/cells8050481 - 20 May 2019

Cited by 54 | Viewed by 11972

Abstract

Patient-derived tumor organoids (PDOs) represent a promising preclinical cancer model that better replicates disease, compared with traditional cell culture models. We have established PDOs from various human tumors to accurately and efficiently recapitulate the tissue architecture and function. Molecular targeted therapies with remarkable [...] Read more.

Patient-derived tumor organoids (PDOs) represent a promising preclinical cancer model that better replicates disease, compared with traditional cell culture models. We have established PDOs from various human tumors to accurately and efficiently recapitulate the tissue architecture and function. Molecular targeted therapies with remarkable efficacy are currently in use against various tumors. Thus, there is a need for in vitro functional-potency assays that can be used to test the efficacy of molecular targeted drugs and model complex interactions between immune cells and tumor cells to evaluate the potential for cancer immunotherapy. This study represents an in vitro evaluation of different classes of molecular targeted drugs, including small-molecule inhibitors, monoclonal antibodies, and an antibody-drug conjugate, using lung PDOs. We evaluated epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) inhibitors using a suitable high-throughput assay system. Next, the antibody-dependent cellular cytotoxicity (ADCC) activity of an anti-HER2 monoclonal antibody was evaluated to visualize the interactions of immune cells with PDOs during ADCC responses. Moreover, an evaluation system was developed for the immune checkpoint inhibitors, nivolumab and pembrolizumab, using PDOs. Our results demonstrate that the in vitro assay systems using PDOs were suitable for evaluating molecular targeted drugs under conditions that better reflect pathological conditions. Full article

(This article belongs to the Special Issue Patient-Derived Cancer Models from Basic Study to Clinical Application)

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12 pages, 3702 KiB

Open AccessEditor’s ChoiceArticle

A Cleared View on Retinal Organoids

by Virginia Cora, Jasmin Haderspeck, Lena Antkowiak, Ulrich Mattheus, Peter H. Neckel, Andreas F. Mack, Sylvia Bolz, Marius Ueffing, Natalia Pashkovskaia, Kevin Achberger and Stefan Liebau

Cells 2019, 8(5), 391; https://doi.org/10.3390/cells8050391 - 28 Apr 2019

Cited by 41 | Viewed by 10251

Abstract

Human induced pluripotent stem cell (hiPSC)-derived organoids mimicking tissues and organs in vitro have advanced medical research, as they opened up new possibilities for in-depth basic research on human organ development as well as providing a human in vitro model for personalized therapeutic [...] Read more.

Human induced pluripotent stem cell (hiPSC)-derived organoids mimicking tissues and organs in vitro have advanced medical research, as they opened up new possibilities for in-depth basic research on human organ development as well as providing a human in vitro model for personalized therapeutic approaches. hiPSC-derived retinal organoids have proven to be of great value for modeling the human retina featuring a very similar cellular composition, layering, and functionality. The technically challenging imaging of three-dimensional structures such as retinal organoids has, however, raised the need for robust whole-organoid imaging techniques. To improve imaging of retinal organoids we optimized a passive clearing technique (PACT), which enables high-resolution visualization of fragile intra-tissue structures. Using cleared retinal organoids, we could greatly enhance the antibody labeling efficiency and depth of imaging at high resolution, thereby improving the three-dimensional microscopy output. In that course, we were able to identify the spatial morphological shape and organization of, e.g., photoreceptor cells and bipolar cell layers. Moreover, we used the synaptic protein CtBP2/Ribeye to visualize the interconnection points of photoreceptor and bipolar cells forming the retinal-specific ribbon synapses. Full article

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

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29 pages, 6468 KiB

Open AccessEditor’s ChoiceArticle

Rainbow Trout Red Blood Cells Exposed to Viral Hemorrhagic Septicemia Virus Up-Regulate Antigen-Processing Mechanisms and MHC I&II, CD86, and CD83 Antigen-presenting Cell Markers

by Ivan Nombela, Ricardo Requena-Platek, Byron Morales-Lange, Veronica Chico, Sara Puente-Marin, Sergio Ciordia, Maria Carmen Mena, Julio Coll, Luis Perez, Luis Mercado and Maria del Mar Ortega-Villaizan

Cells 2019, 8(5), 386; https://doi.org/10.3390/cells8050386 - 27 Apr 2019

Cited by 32 | Viewed by 8857

Abstract

Nucleated teleost red blood cells (RBCs) are known to express molecules from the major histocompatibility complex and peptide-generating processes such as autophagy and proteasomes, but the role of RBCs in antigen presentation of viruses have not been studied yet. In this study, RBCs [...] Read more.

Nucleated teleost red blood cells (RBCs) are known to express molecules from the major histocompatibility complex and peptide-generating processes such as autophagy and proteasomes, but the role of RBCs in antigen presentation of viruses have not been studied yet. In this study, RBCs exposed ex vivo to viral hemorrhagic septicemia virus (VHSV) were evaluated by means of transcriptomic and proteomic approaches. Genes and proteins related to antigen presentation molecules, proteasome degradation, and autophagy were up-regulated. VHSV induced accumulation of ubiquitinated proteins in ex vivo VHSV-exposed RBCs and showed at the same time a decrease of proteasome activity. Furthermore, induction of autophagy was detected by evaluating LC3 protein levels. Sequestosome-1/p62 underwent degradation early after VHSV exposure, and it may be a link between ubiquitination and autophagy activation. Inhibition of autophagosome degradation with niclosamide resulted in intracellular detection of N protein of VHSV (NVHSV) and p62 accumulation. In addition, antigen presentation cell markers, such as major histocompatibility complex (MHC) class I & II, CD83, and CD86, increased at the transcriptional and translational level in rainbow trout RBCs exposed to VHSV. In summary, we show that nucleated rainbow trout RBCs can degrade VHSV while displaying an antigen-presenting cell (APC)-like profile. Full article

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18 pages, 2571 KiB

Open AccessEditor’s ChoiceArticle

MAGI1 Mediates eNOS Activation and NO Production in Endothelial Cells in Response to Fluid Shear Stress

by Kedar Ghimire, Jelena Zaric, Begoña Alday-Parejo, Jochen Seebach, Mélanie Bousquenaud, Jimmy Stalin, Grégory Bieler, Hans-Joachim Schnittler and Curzio Rüegg

Cells 2019, 8(5), 388; https://doi.org/10.3390/cells8050388 - 27 Apr 2019

Cited by 44 | Viewed by 8772

Abstract

Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain [...] Read more.

Fluid shear stress stimulates endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production through multiple kinases, including protein kinase A (PKA), AMP-activated protein kinase (AMPK), AKT and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an adaptor protein that stabilizes epithelial and endothelial cell-cell contacts. The aim of this study was to assess the unknown role of endothelial cell MAGI1 in response to fluid shear stress. We show constitutive expression and co-localization of MAGI1 with vascular endothelial cadherin (VE-cadherin) in endothelial cells at cellular junctions under static and laminar flow conditions. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbed flow-dependent responses, specifically, Krüppel-like factor 4 (KLF4) expression, endothelial cell alignment, eNOS phosphorylation and NO production. MAGI1 overexpression had opposite effects and induced phosphorylation of PKA, AMPK, and CAMKII. Pharmacological inhibition of PKA and AMPK prevented MAGI1-mediated eNOS phosphorylation. Consistently, MAGI1 silencing and PKA inhibition suppressed the flow-induced NO production. Endothelial cell-specific transgenic expression of MAGI1 induced PKA and eNOS phosphorylation in vivo and increased NO production ex vivo in isolated endothelial cells. In conclusion, we have identified endothelial cell MAGI1 as a previously unrecognized mediator of fluid shear stress-induced and PKA/AMPK dependent eNOS activation and NO production. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis of Cardiovascular Disease)

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14 pages, 1811 KiB

Open AccessEditor’s ChoiceArticle

Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models

by Heng Sheng Sow, Jiang Ren, Marcel Camps, Ferry Ossendorp and Peter ten Dijke

Cells 2019, 8(4), 320; https://doi.org/10.3390/cells8040320 - 5 Apr 2019

Cited by 91 | Viewed by 11771

Abstract

Antibodies blocking the programmed death-ligand 1 (PD-L1) have shown impressive and durable responses in clinical studies. However, this type of immunotherapy is only effective in a subset of patients and not sufficient for rejection of all tumor types. In this study, we explored [...] Read more.

Antibodies blocking the programmed death-ligand 1 (PD-L1) have shown impressive and durable responses in clinical studies. However, this type of immunotherapy is only effective in a subset of patients and not sufficient for rejection of all tumor types. In this study, we explored in two mouse tumor models whether the antitumor effect could be enhanced by the combined blockade of PD-L1 and transforming growth factor-β (TGF-β), a potent immunosuppressive cytokine. The effect of anti-PD-L1 mouse monoclonal (mAb) and a TGF-β type I receptor small molecule kinase inhibitor (LY364947) was evaluated in the highly immunogenic mouse MC38 colon adenocarcinoma and the poorly immunogenic mouse KPC1 pancreatic tumor model. In the MC38 tumor model, LY364947 monotherapy did not show any antitumor effect, whereas treatment with anti-PD-L1 mAb significantly delayed tumor outgrowth. However, combination therapy showed the strongest therapeutic efficacy, resulting in improved long-term survival compared with anti-PD-L1 mAb monotherapy. This improved survival was associated with an increased influx of CD8⁺ T cells in the tumor microenvironment. In the KPC1 tumor model, LY364947 did not enhance the antitumor effect of anti-PD-L1 mAb. Despite this, delayed KPC1 tumor outgrowth was observed in the LY364947-treated group and this treatment led to a significant reduction of CD4⁺ T cells in the tumor microenvironment. Together, our data indicate that an additive anti-tumor response of dual targeting PD-L1 and TGF-β is dependent on the tumor model used, highlighting the importance of selecting appropriate cancer types, using in-depth analysis of the tumor microenvironment, which can benefit from combinatorial immunotherapy regimens. Full article

(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)

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17 pages, 14461 KiB

Open AccessEditor’s ChoiceArticle

Hepatitis C Virus Non-Structural Protein 5A (NS5A) Disrupts Mitochondrial Dynamics and Induces Mitophagy

by Alagie Jassey, Ching-Hsuan Liu, Chun A. Changou, Christopher D. Richardson, Hsue-Yin Hsu and Liang-Tzung Lin

Cells 2019, 8(4), 290; https://doi.org/10.3390/cells8040290 - 29 Mar 2019

Cited by 59 | Viewed by 7298

Abstract

Mitophagy is a selective form of autophagy, targeting damaged mitochondria for lysosomal degradation. Although HCV infection has been shown to induce mitophagy, the precise underlying mechanism and the effector protein responsible remain unclear. Herein, we demonstrated that the HCV non-structural protein 5A (NS5A) [...] Read more.

Mitophagy is a selective form of autophagy, targeting damaged mitochondria for lysosomal degradation. Although HCV infection has been shown to induce mitophagy, the precise underlying mechanism and the effector protein responsible remain unclear. Herein, we demonstrated that the HCV non-structural protein 5A (NS5A) plays a key role in regulating cellular mitophagy. Specifically, the expression of HCV NS5A in the hepatoma cells triggered hallmarks of mitophagy including mitochondrial fragmentation, loss of mitochondrial membrane potential, and Parkin translocation to the mitochondria. Furthermore, mitophagy induction through the expression of NS5A led to an increase in autophagic flux as demonstrated by an accumulation of LC3II in the presence of bafilomycin and a time-dependent decrease in p62 protein level. Intriguingly, the expression of NS5A concomitantly enhanced reactive oxygen species (ROS) production, and treatment with an antioxidant attenuated the NS5A-induced mitophagy event. These phenomena are similarly recapitulated in the NS5A-expressing HCV subgenomic replicon cells. Finally, we demonstrated that expression of HCV core, which has been documented to inhibit mitophagy, blocked the mitophagy induction both in cells harboring HCV replicating subgenomes or expressing NS5A alone. Our results, therefore, identified a new role for NS5A as an important regulator of HCV-induced mitophagy and have implications to broadening our understanding of the HCV-mitophagy interplay. Full article

(This article belongs to the Special Issue Hepatitis C Virus and Host Interactions)

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15 pages, 2863 KiB

Open AccessEditor’s ChoiceArticle

Novel Flavivirus Antiviral That Targets the Host Nuclear Transport Importin α/β1 Heterodimer

by Sundy N. Y. Yang, Sarah C. Atkinson, Johanna E. Fraser, Chunxiao Wang, Belinda Maher, Noelia Roman, Jade K. Forwood, Kylie M. Wagstaff, Natalie A. Borg and David A. Jans

Cells 2019, 8(3), 281; https://doi.org/10.3390/cells8030281 - 24 Mar 2019

Cited by 39 | Viewed by 8265

Abstract

Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective vaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in the infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin [...] Read more.

Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective vaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in the infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin (IMP) α/β1 proteins. Here, we used a range of microscopic, virological and biochemical/biophysical approaches to show for the first time that the small molecule GW5074 has anti-DENV action through its novel ability to inhibit NS5–IMPα/β1 interaction in vitro as well as NS5 nuclear localisation in infected cells. Strikingly, GW5074 not only inhibits IMPα binding to IMPβ1, but can dissociate preformed IMPα/β1 heterodimer, through targeting the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity, as shown using analytical ultracentrifugation, thermostability analysis and circular dichroism measurements. Importantly, GW5074 has strong antiviral activity at low µM concentrations against not only DENV-2, but also zika virus and West Nile virus. This work highlights DENV NS5 nuclear targeting as a viable target for anti-flaviviral therapeutics. Full article

(This article belongs to the Special Issue Nuclear Transport in Ageing and Diseases)

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12 pages, 3836 KiB

Open AccessEditor’s ChoiceArticle

Promethin Is a Conserved Seipin Partner Protein

by Inês G. Castro, Michal Eisenberg-Bord, Elisa Persiani, Justin J. Rochford, Maya Schuldiner and Maria Bohnert

Cells 2019, 8(3), 268; https://doi.org/10.3390/cells8030268 - 21 Mar 2019

Cited by 54 | Viewed by 7696

Abstract

Seipin (BSCL2/SPG17) is a key factor in lipid droplet (LD) biology, and its dysfunction results in severe pathologies, including the fat storage disease Berardinelli-Seip congenital lipodystrophy type 2, as well as several neurological seipinopathies. Despite its importance for human health, the molecular role [...] Read more.

Seipin (BSCL2/SPG17) is a key factor in lipid droplet (LD) biology, and its dysfunction results in severe pathologies, including the fat storage disease Berardinelli-Seip congenital lipodystrophy type 2, as well as several neurological seipinopathies. Despite its importance for human health, the molecular role of seipin is still enigmatic. Seipin is evolutionarily conserved from yeast to humans. In yeast, seipin was recently found to cooperate with the lipid droplet organization (LDO) proteins, Ldo16 and Ldo45, two structurally-related proteins involved in LD function and identity that display remote homology to the human protein promethin/TMEM159. In this study, we show that promethin is indeed an LD-associated protein that forms a complex with seipin, and its localization to the LD surface can be modulated by seipin expression levels. We thus identify promethin as a novel seipin partner protein. Full article

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13 pages, 2513 KiB

Open AccessEditor’s ChoiceArticle

Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo

by Maximilian G. Christ, Heike Huesmann, Heike Nagel, Andreas Kern and Christian Behl

Cells 2019, 8(3), 211; https://doi.org/10.3390/cells8030211 - 2 Mar 2019

Cited by 53 | Viewed by 12668

Abstract

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and [...] Read more.

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer’s disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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17 pages, 6930 KiB

Open AccessEditor’s ChoiceArticle

Anti-Inflammatory Effect of Sulforaphane on LPS-Activated Microglia Potentially through JNK/AP-1/NF-κB Inhibition and Nrf2/HO-1 Activation

by Lalita Subedi, Jae Hyuk Lee, Silvia Yumnam, Eunhee Ji and Sun Yeou Kim

Cells 2019, 8(2), 194; https://doi.org/10.3390/cells8020194 - 22 Feb 2019

Cited by 227 | Viewed by 13659

Abstract

Sulforaphane (SFN), a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator, is present in the species of the Brassicaceae, especially in broccoli sprouts. In this study, the effects of SFN against microglial activation and inflammation, and the potential mechanisms involved, were analyzed. [...] Read more.

Sulforaphane (SFN), a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator, is present in the species of the Brassicaceae, especially in broccoli sprouts. In this study, the effects of SFN against microglial activation and inflammation, and the potential mechanisms involved, were analyzed. As mitogen-activated protein kinase (MAPK) signaling plays a key role in microglial activation and inflammation, we focused on the role of SFN in regulating the MAPK signaling regulation of the inflammatory and anti-inflammatory cascades in lipopolysaccharide (LPS)-activated microglia. The anti-inflammatory and immunomodulatory effects of SFN were explored by evaluating the expression and secretion of inflammatory proteins, cytokines, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and activator protein-1 (AP-1) under pre- and post-treatment conditions. Under the SFN pre- and post-treatment conditions, the MAPK phosphorylation levels were significantly reduced in both acutely and chronically activated microglial cells. SFN also reduced the c-Jun N-terminal kinase (JNK) phosphorylation levels, which subsequently reduced NF-κB and AP-1 signaling. As a result, the expression of the inflammatory mediators (iNOS, COX-2, NO, and PGE2) and proinflammatory cytokines (TNF-α, IL-6, and IL-1β) was decreased. At the same time, SFN increased the expression of Nrf2 and heme oxygenase-1 (HO-1) as well as the production of the anti-inflammatory cytokines IL-10 and IL-4. In conclusion, this study demonstrated that SFN exerts an anti-neuroinflammatory effect on microglia through JNK/AP-1/NF-κB pathway inhibition and Nrf2/HO-1 pathway activation. Full article

(This article belongs to the Section Cell Signaling)

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16 pages, 2520 KiB

Open AccessEditor’s ChoiceArticle

Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation

by Brandon C. Farmer, Jude Kluemper and Lance A. Johnson

Cells 2019, 8(2), 182; https://doi.org/10.3390/cells8020182 - 20 Feb 2019

Cited by 127 | Viewed by 15273

Abstract

Lipid droplets (LDs) serve as energy rich reservoirs and have been associated with apolipoprotein E (APOE) and neurodegeneration. The E4 allele of APOE (E4) is the strongest genetic risk factor for the development of late onset Alzheimer’s disease (AD). Since both [...] Read more.

Lipid droplets (LDs) serve as energy rich reservoirs and have been associated with apolipoprotein E (APOE) and neurodegeneration. The E4 allele of APOE (E4) is the strongest genetic risk factor for the development of late onset Alzheimer’s disease (AD). Since both E4 carriers and individuals with AD exhibit a state of cerebral lipid dyshomeostasis, we hypothesized that APOE may play a role in regulating LD metabolism. We found that astrocytes expressing E4 accumulate significantly more and smaller LDs compared to E3 astrocytes. Accordingly, expression of perilipin-2, an essential LD protein component, was higher in E4 astrocytes. We then probed fatty acid (FA) metabolism and found E4 astrocytes to exhibit decreased uptake of palmitate, and decreased oxidation of exogenously supplied oleate and palmitate. We then measured oxygen consumption rate, and found E4 astrocytes to consume more oxygen for endogenous FA oxidation and accumulate more LD-derived metabolites due to incomplete oxidation. Lastly, we found that E4 astrocytes are more sensitive to carnitine palmitoyltransferase-1 inhibition than E3 astrocytes. These findings offer the potential for further studies investigating the link between astrocyte lipid storage, utilization, and neurodegenerative disease as a function of APOE genotype. Full article

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23 pages, 2225 KiB

Open AccessEditor’s ChoiceArticle

Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1

by Giuseppe Caruso, Claudia G. Fresta, Nicolò Musso, Mariaconcetta Giambirtone, Margherita Grasso, Simona F. Spampinato, Sara Merlo, Filippo Drago, Giuseppe Lazzarino, Maria A. Sortino, Susan M. Lunte and Filippo Caraci

Cells 2019, 8(1), 64; https://doi.org/10.3390/cells8010064 - 17 Jan 2019

Cited by 109 | Viewed by 10067

Abstract

Carnosine (β-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aβ) aggregation and the scavenging of reactive species. Microglia play [...] Read more.

Carnosine (β-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aβ) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer’s disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals. However, the effects of carnosine on microglial cells and neuroinflammation are not well understood. In the present work, carnosine was tested for its ability to protect BV-2 microglial cells against oligomeric Aβ1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with Aβ oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O₂^−• intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1β, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1. Carnosine also prevented Aβ-induced neurodegeneration in mixed neuronal cultures challenged with Aβ oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-β receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against Aβ toxicity with a key role of TGF-β1 in mediating these protective effects. Full article

(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)

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23 pages, 10506 KiB

Open AccessEditor’s ChoiceArticle

Oxidative Stress Induces Telomere Dysfunction and Senescence by Replication Fork Arrest

by Elisa Coluzzi, Stefano Leone and Antonella Sgura

Cells 2019, 8(1), 19; https://doi.org/10.3390/cells8010019 - 3 Jan 2019

Cited by 116 | Viewed by 10843

Abstract

Oxidative DNA damage, particularly 8-oxoguanine, represents the most frequent DNA damage in human cells, especially at the telomeric level. The presence of oxidative lesions in the DNA can hinder the replication fork and is able to activate the DNA damage response. In this [...] Read more.

Oxidative DNA damage, particularly 8-oxoguanine, represents the most frequent DNA damage in human cells, especially at the telomeric level. The presence of oxidative lesions in the DNA can hinder the replication fork and is able to activate the DNA damage response. In this study, we wanted to understand the mechanisms by which oxidative damage causes telomere dysfunction and senescence in human primary fibroblasts. After acute oxidative stress at telomeres, our data demonstrated a reduction in TRF1 and TRF2, which are involved in proper telomere replication and T-loop formation, respectively. Furthermore, we observed a higher level of γH2AX with respect to 53BP1 at telomeres, suggesting a telomeric replication fork stall rather than double-strand breaks. To confirm this finding, we studied the replication of telomeres by Chromosome Orientation-FISH (CO-FISH). The data obtained show an increase in unreplicated telomeres after hydrogen peroxide treatment, corroborating the idea that the presence of 8-oxoG can induce replication fork arrest at telomeres. Lastly, we analyzed the H3K9me3 histone mark after oxidative stress at telomeres, and our results showed an increase of this marker, most likely inducing the heterochromatinization of telomeres. These results suggest that 8-oxoG is fundamental in oxidative stress-induced telomeric damage, principally causing replication fork arrest. Full article

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19 pages, 4251 KiB

Open AccessEditor’s ChoiceArticle

A Rise in ATP, ROS, and Mitochondrial Content upon Glucose Withdrawal Correlates with a Dysregulated Mitochondria Turnover Mediated by the Activation of the Protein Deacetylase SIRT1

by Seon Beom Song and Eun Seong Hwang

Cells 2019, 8(1), 11; https://doi.org/10.3390/cells8010011 - 27 Dec 2018

Cited by 37 | Viewed by 10656

Abstract

Glucose withdrawal has been used as a model for the study of homeostatic defense mechanisms, especially for how cells cope with a shortage of nutrient supply by enhancing catabolism. However, detailed cellular responses to glucose withdrawal have been poorly studied, and are controversial. [...] Read more.

Glucose withdrawal has been used as a model for the study of homeostatic defense mechanisms, especially for how cells cope with a shortage of nutrient supply by enhancing catabolism. However, detailed cellular responses to glucose withdrawal have been poorly studied, and are controversial. In this study, we determined how glucose withdrawal affects mitochondrial activity, and the quantity and the role of SIRT1 in these changes. The results of our study indicate a substantial increase in ATP production from mitochondria, through an elevation of mitochondrial biogenesis, mediated by SIRT1 activation that is driven by increased NAD⁺/NADH ratio. Moreover, mitochondria persisted in the cells as elongated forms, and apparently evaded mitophagic removal. This led to a steady increase in mitochondria content and the reactive oxygen species (ROS) generated from them, indicating failure in ATP and ROS homeostasis, due to a misbalance in SIRT1-mediated mitochondria turnover in conditions of glucose withdrawal. Our results suggest that SIRT1 activation alone cannot properly manage energy homeostasis under certain metabolic crisis conditions. Full article

(This article belongs to the Special Issue Mitochondrial Biology in Health and Disease)

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Review

23 pages, 398 KiB

Open AccessEditor’s ChoiceReview

The Genetic Basis of Non-Contact Soft Tissue Injuries-Are There Practical Applications of Genetic Knowledge?

by Beata Borzemska, Paweł Cięszczyk and Cezary Żekanowski

Cells 2024, 13(22), 1828; https://doi.org/10.3390/cells13221828 - 5 Nov 2024

Viewed by 2464

Abstract

Physical activity increases the risk of non-contact injuries, mainly affecting muscles, tendons, and ligaments. Genetic factors are recognized as contributing to susceptibility to different types of soft tissue injuries, making this broad condition a complicated multifactorial entity. Understanding genetic predisposition seems to offer [...] Read more.

Physical activity increases the risk of non-contact injuries, mainly affecting muscles, tendons, and ligaments. Genetic factors are recognized as contributing to susceptibility to different types of soft tissue injuries, making this broad condition a complicated multifactorial entity. Understanding genetic predisposition seems to offer the potential for personalized injury prevention and improved recovery strategies. The candidate gene analysis approach used so far, has often yielded inconclusive results. This manuscript reviews the most commonly studied genetic variants in genes involved in the musculoskeletal system’s structure and recovery processes (ACTN3, ACE, CKM, MLCK, AMPD1, IGF2, IL6, TNFα, CCL2, COL1A1, COL5A1, MMP3, and TNC). Referring to the literature, it was highlighted that single-gene analyses provide limited insight. On the other hand, novel genetic testing methods identify numerous variants of uncertain physiological relevance. Distinguishing between functionally important variants, modifying variants, and the thousands of irrelevant variants requires advanced bioinformatics methods and basic multiomics research to identify the key biological pathways contributing to injury susceptibility. Tools like the Total Genotype Score (TGS) and Polygenic Risk Score (PRS) offer a more holistic view by assessing the combined effect of multiple variants. However, these methods, while useful in research, lack clinical applicability. In conclusion, it is too early to determine the clinical implications of genetic variability as a tool for improving well-established training and injury prevention methods, as the predictive power of genetic testing for injury predisposition is currently low. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Musculoskeletal and Other Tissue Injuries and Disruptions—Regenerative Potential of Exercise)

24 pages, 2902 KiB

Open AccessEditor’s ChoiceReview

Advancing CRISPR-Based Solutions for COVID-19 Diagnosis and Therapeutics

by Roaa Hadi, Abhishek Poddar, Shivakumar Sonnaila, Venkata Suryanarayana Murthy Bhavaraju and Shilpi Agrawal

Cells 2024, 13(21), 1794; https://doi.org/10.3390/cells13211794 - 30 Oct 2024

Cited by 1 | Viewed by 3413

Abstract

Since the onset of the COVID-19 pandemic, a variety of diagnostic approaches, including RT-qPCR, RAPID, and LFA, have been adopted, with RT-qPCR emerging as the gold standard. However, a significant challenge in COVID-19 diagnostics is the wide range of symptoms presented by patients, [...] Read more.

Since the onset of the COVID-19 pandemic, a variety of diagnostic approaches, including RT-qPCR, RAPID, and LFA, have been adopted, with RT-qPCR emerging as the gold standard. However, a significant challenge in COVID-19 diagnostics is the wide range of symptoms presented by patients, necessitating early and accurate diagnosis for effective management. Although RT-qPCR is a precise molecular technique, it is not immune to false-negative results. In contrast, CRISPR-based detection methods for SARS-CoV-2 offer several advantages: they are cost-effective, time-efficient, highly sensitive, and specific, and they do not require sophisticated instruments. These methods also show promise for scalability, enabling diagnostic tests. CRISPR technology can be customized to target any genomic region of interest, making it a versatile tool with applications beyond diagnostics, including therapeutic development. The CRISPR/Cas systems provide precise gene targeting with immense potential for creating next-generation diagnostics and therapeutics. One of the key advantages of CRISPR/Cas-based therapeutics is the ability to perform multiplexing, where different sgRNAs or crRNAs can target multiple sites within the same gene, reducing the likelihood of viral escape mutants. Among the various CRISPR systems, CRISPR/Cas13 and CARVER (Cas13-assisted restriction of viral expression and readout) are particularly promising. These systems can target a broad range of single-stranded RNA viruses, making them suitable for the diagnosis and treatment of various viral diseases, including SARS-CoV-2. However, the efficacy and safety of CRISPR-based therapeutics must be thoroughly evaluated in pre-clinical and clinical settings. While CRISPR biotechnologies have not yet been fully harnessed to control the current COVID-19 pandemic, there is an optimism that the limitations of the CRISPR/Cas system can be overcome soon. This review discusses how CRISPR-based strategies can revolutionize disease diagnosis and therapeutic development, better preparing us for future viral threats. Full article

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19 pages, 759 KiB

Open AccessEditor’s ChoiceReview

Hepatocellular-Carcinoma-Derived Organoids: Innovation in Cancer Research

by Carlo Airola, Maria Pallozzi, Eleonora Cesari, Lucia Cerrito, Leonardo Stella, Claudio Sette, Felice Giuliante, Antonio Gasbarrini and Francesca Romana Ponziani

Cells 2024, 13(20), 1726; https://doi.org/10.3390/cells13201726 - 18 Oct 2024

Cited by 5 | Viewed by 3057

Abstract

Hepatocellular carcinomas (HCCs) are highly heterogeneous malignancies. They are characterized by a peculiar tumor microenvironment and dense vascularization. The importance of signaling between immune cells, endothelial cells, and tumor cells leads to the difficult recapitulation of a reliable in vitro HCC model using [...] Read more.

Hepatocellular carcinomas (HCCs) are highly heterogeneous malignancies. They are characterized by a peculiar tumor microenvironment and dense vascularization. The importance of signaling between immune cells, endothelial cells, and tumor cells leads to the difficult recapitulation of a reliable in vitro HCC model using the conventional two-dimensional cell cultures. The advent of three-dimensional organoid tumor technology has revolutionized our understanding of the pathogenesis and progression of several malignancies by faithfully replicating the original cancer genomic, epigenomic, and microenvironmental landscape. Organoids more closely mimic the in vivo environment and cell interactions, replicating factors such as the spatial organization of cell surface receptors and gene expression, and will probably become an important tool in the choice of therapies and the evaluation of tumor response to treatments. This review aimed to describe the ongoing and potential applications of organoids as an in vitro model for the study of HCC development, its interaction with the host’s immunity, the analysis of drug sensitivity tests, and the current limits in this field. Full article

(This article belongs to the Special Issue Liver Constituent Cells: Their Niche, Close Intercellular Relationship and Crosstalk with the Extracellular Environment—Current and Future Perspectives (2nd Edition))

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21 pages, 6630 KiB

Open AccessEditor’s ChoiceReview

Application of Single Cell Type-Derived Spheroids Generated by Using a Hanging Drop Culture Technique in Various In Vitro Disease Models: A Narrow Review

by Hiroshi Ohguro, Megumi Watanabe, Tatsuya Sato, Nami Nishikiori, Araya Umetsu, Megumi Higashide, Toshiyuki Yano, Hiromu Suzuki, Akihiro Miyazaki, Kohichi Takada, Hisashi Uhara, Masato Furuhashi and Fumihito Hikage

Cells 2024, 13(18), 1549; https://doi.org/10.3390/cells13181549 - 14 Sep 2024

Cited by 7 | Viewed by 2711

Abstract

Cell culture methods are indispensable strategies for studies in biological sciences and for drug discovery and testing. Most cell cultures have been developed using two-dimensional (2D) culture methods, but three-dimensional (3D) culture techniques enable the establishment of in vitro models that replicate various [...] Read more.

Cell culture methods are indispensable strategies for studies in biological sciences and for drug discovery and testing. Most cell cultures have been developed using two-dimensional (2D) culture methods, but three-dimensional (3D) culture techniques enable the establishment of in vitro models that replicate various pathogenic conditions and they provide valuable insights into the pathophysiology of various diseases as well as more precise results in tests for drug efficacy. However, one difficulty in the use of 3D cultures is selection of the appropriate 3D cell culture technique for the study purpose among the various techniques ranging from the simplest single cell type-derived spheroid culture to the more sophisticated organoid cultures. In the simplest single cell type-derived spheroid cultures, there are also various scaffold-assisted methods such as hydrogel-assisted cultures, biofilm-assisted cultures, particle-assisted cultures, and magnet particle-assisted cultures, as well as non-assisted methods, such as static suspension cultures, floating cultures, and hanging drop cultures. Since each method can be differently influenced by various factors such as gravity force, buoyant force, centrifugal force, and magnetic force, in addition to non-physiological scaffolds, each method has its own advantages and disadvantages, and the methods have different suitable applications. We have been focusing on the use of a hanging drop culture method for modeling various non-cancerous and cancerous diseases because this technique is affected only by gravity force and buoyant force and is thus the simplest method among the various single cell type-derived spheroid culture methods. We have found that the biological natures of spheroids generated even by the simplest method of hanging drop cultures are completely different from those of 2D cultured cells. In this review, we focus on the biological aspects of single cell type-derived spheroid culture and its applications in in vitro models for various diseases. Full article

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21 pages, 1753 KiB

Open AccessEditor’s ChoiceReview

V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities

by Antonio Falace, Greta Volpedo, Marcello Scala, Federico Zara, Pasquale Striano and Anna Fassio

Cells 2024, 13(17), 1441; https://doi.org/10.3390/cells13171441 - 28 Aug 2024

Cited by 4 | Viewed by 3581

Abstract

Vacuolar-type ATPase (v-ATPase) is a multimeric protein complex that regulates H⁺ transport across membranes and intra-cellular organelle acidification. Catabolic processes, such as endocytic degradation and autophagy, strictly rely on v-ATPase-dependent luminal acidification in lysosomes. The v-ATPase complex is expressed at high levels [...] Read more.

Vacuolar-type ATPase (v-ATPase) is a multimeric protein complex that regulates H⁺ transport across membranes and intra-cellular organelle acidification. Catabolic processes, such as endocytic degradation and autophagy, strictly rely on v-ATPase-dependent luminal acidification in lysosomes. The v-ATPase complex is expressed at high levels in the brain and its impairment triggers neuronal dysfunction and neurodegeneration. Due to their post-mitotic nature and highly specialized function and morphology, neurons display a unique vulnerability to lysosomal dyshomeostasis. Alterations in genes encoding subunits composing v-ATPase or v-ATPase-related proteins impair brain development and synaptic function in animal models and underlie genetic diseases in humans, such as encephalopathies, epilepsy, as well as neurodevelopmental, and degenerative disorders. This review presents the genetic and functional evidence linking v-ATPase subunits and accessory proteins to various brain disorders, from early-onset developmental epileptic encephalopathy to neurodegenerative diseases. We highlight the latest emerging therapeutic strategies aimed at mitigating lysosomal defects associated with v-ATPase dysfunction. Full article

(This article belongs to the Special Issue Understanding the Interplay Between Autophagy and Neurodegeneration)

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29 pages, 2202 KiB

Open AccessEditor’s ChoiceReview

Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging

by Gérald J. Prud’homme and Qinghua Wang

Cells 2024, 13(17), 1413; https://doi.org/10.3390/cells13171413 - 24 Aug 2024

Cited by 19 | Viewed by 7998

Abstract

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have [...] Read more.

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer’s disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications. Full article

(This article belongs to the Section Tissues and Organs)

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16 pages, 2568 KiB

Open AccessEditor’s ChoiceReview

Molecular Mechanisms of Autophagy Decline during Aging

by Shaun H. Y. Lim, Malene Hansen and Caroline Kumsta

Cells 2024, 13(16), 1364; https://doi.org/10.3390/cells13161364 - 16 Aug 2024

Cited by 9 | Viewed by 5410

Abstract

Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. [...] Read more.

Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age. In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy. Full article

(This article belongs to the Special Issue Autophagy Meets Aging 2025)

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16 pages, 1262 KiB

Open AccessEditor’s ChoiceReview

Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance

by Young Keun Hwang, Dong-Hun Lee, Eun Chae Lee and Jae Sang Oh

Cells 2024, 13(16), 1332; https://doi.org/10.3390/cells13161332 - 11 Aug 2024

Cited by 7 | Viewed by 3153

Abstract

Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling [...] Read more.

Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival. Full article

(This article belongs to the Section Autophagy)

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24 pages, 663 KiB

Open AccessEditor’s ChoiceReview

In Silico Deciphering of the Potential Impact of Variants of Uncertain Significance in Hereditary Colorectal Cancer Syndromes

by Candida Fasano, Martina Lepore Signorile, Katia De Marco, Giovanna Forte, Vittoria Disciglio, Paola Sanese, Valentina Grossi and Cristiano Simone

Cells 2024, 13(16), 1314; https://doi.org/10.3390/cells13161314 - 6 Aug 2024

Cited by 4 | Viewed by 2324

Abstract

Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis [...] Read more.

Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes. Full article

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32 pages, 1003 KiB

Open AccessEditor’s ChoiceReview

Molecular Mechanisms and Clinical Application of Multipotent Stem Cells for Spinal Cord Injury

by Michał Szymoniuk, Jakub Litak, Leon Sakwa, Aleksandra Dryla, Wojciech Zezuliński, Wojciech Czyżewski, Piotr Kamieniak and Tomasz Blicharski

Cells 2023, 12(1), 120; https://doi.org/10.3390/cells12010120 - 28 Dec 2022

Cited by 27 | Viewed by 6610

Abstract

Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well as urinary complications, and a small number [...] Read more.

Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well as urinary complications, and a small number of patients experience a complete recovery. Current standard treatment modalities of the SCI aim to prevent secondary injury and provide limited recovery of lost neurological functions. Stem Cell Therapy (SCT) represents an emerging treatment approach using the differentiation, paracrine, and self-renewal capabilities of stem cells to regenerate the injured spinal cord. To date, multipotent stem cells including mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) represent the most investigated types of stem cells for the treatment of SCI in preclinical and clinical studies. The microenvironment of SCI has a significant impact on the survival, proliferation, and differentiation of transplanted stem cells. Therefore, a deep understanding of the pathophysiology of SCI and molecular mechanisms through which stem cells act may help improve the treatment efficacy of SCT and find new therapeutic approaches such as stem-cell-derived exosomes, gene-modified stem cells, scaffolds, and nanomaterials. In this literature review, the pathogenesis of SCI and molecular mechanisms of action of multipotent stem cells including MSCs, NSCs, and HSCs are comprehensively described. Moreover, the clinical efficacy of multipotent stem cells in SCI treatment, an optimal protocol of stem cell administration, and recent therapeutic approaches based on or combined with SCT are also discussed. Full article

(This article belongs to the Special Issue Neural Repair of the Central Nervous System: Stem Cells and Other Approaches)

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22 pages, 1310 KiB

Open AccessEditor’s ChoiceReview

The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology

by Isaure Vanmeerbeek, Jannes Govaerts, Raquel S. Laureano, Jenny Sprooten, Stefan Naulaerts, Daniel M. Borras, Damya Laoui, Massimiliano Mazzone, Jo A. Van Ginderachter and Abhishek D. Garg

Cells 2022, 11(23), 3890; https://doi.org/10.3390/cells11233890 - 2 Dec 2022

Cited by 18 | Viewed by 7487

Abstract

Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer [...] Read more.

Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies. Full article

(This article belongs to the Special Issue Immunogenic Cell Stress and Death)

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18 pages, 1837 KiB

Open AccessEditor’s ChoiceReview

A Review on Autophagy in Orofacial Neuropathic Pain

by Mayank Shrivastava and Liang Ye

Cells 2022, 11(23), 3842; https://doi.org/10.3390/cells11233842 - 30 Nov 2022

Cited by 6 | Viewed by 3066

Abstract

Orofacial neuropathic pain indicates pain caused by a lesion or diseases of the somatosensory nervous system. It is challenging for the clinician to diagnose and manage orofacial neuropathic pain conditions due to the considerable variability between individual clinical presentations and a lack of [...] Read more.

Orofacial neuropathic pain indicates pain caused by a lesion or diseases of the somatosensory nervous system. It is challenging for the clinician to diagnose and manage orofacial neuropathic pain conditions due to the considerable variability between individual clinical presentations and a lack of understanding of the mechanisms underlying the etiology and pathogenesis. In the last few decades, researchers have developed diagnostic criteria, questionnaires, and clinical assessment methods for the diagnosis of orofacial neuropathic pain. Recently, researchers have observed the role of autophagy in neuronal dysfunction as well as in the modulation of neuropathic pain. On this basis, in the present review, we highlight the characteristics, classification, and clinical assessment of orofacial neuropathic pain. Additionally, we introduce autophagy and its potential role in the modulation of orofacial neuropathic pain, along with a brief overview of the pathogenesis, which in future may reveal new possible targets for treating this condition. Full article

(This article belongs to the Special Issue Exclusive Review Papers in Autophagy)

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31 pages, 3152 KiB

Open AccessEditor’s ChoiceReview

Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy

by Rashedul Alam, Mohammad Fazlul Kabir, Hyung-Ryong Kim and Han-Jung Chae

Cells 2022, 11(23), 3773; https://doi.org/10.3390/cells11233773 - 25 Nov 2022

Cited by 8 | Viewed by 4543

Abstract

Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged [...] Read more.

Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment. Full article

(This article belongs to the Special Issue Autophagy and Human Cancers)

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42 pages, 1992 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology

by Aleš Cvekl and Michael John Camerino

Cells 2022, 11(21), 3516; https://doi.org/10.3390/cells11213516 - 6 Nov 2022

Cited by 11 | Viewed by 4799

Abstract

In vitro differentiation of human pluripotent stem cells (hPSCs) into specialized tissues and organs represents a powerful approach to gain insight into those cellular and molecular mechanisms regulating human development. Although normal embryonic eye development is a complex process, generation of ocular organoids [...] Read more.

In vitro differentiation of human pluripotent stem cells (hPSCs) into specialized tissues and organs represents a powerful approach to gain insight into those cellular and molecular mechanisms regulating human development. Although normal embryonic eye development is a complex process, generation of ocular organoids and specific ocular tissues from pluripotent stem cells has provided invaluable insights into the formation of lineage-committed progenitor cell populations, signal transduction pathways, and self-organization principles. This review provides a comprehensive summary of recent advances in generation of adenohypophyseal, olfactory, and lens placodes, lens progenitor cells and three-dimensional (3D) primitive lenses, “lentoid bodies”, and “micro-lenses”. These cells are produced alone or “community-grown” with other ocular tissues. Lentoid bodies/micro-lenses generated from human patients carrying mutations in crystallin genes demonstrate proof-of-principle that these cells are suitable for mechanistic studies of cataractogenesis. Taken together, current and emerging advanced in vitro differentiation methods pave the road to understand molecular mechanisms of cataract formation caused by the entire spectrum of mutations in DNA-binding regulatory genes, such as PAX6, SOX2, FOXE3, MAF, PITX3, and HSF4, individual crystallins, and other genes such as BFSP1, BFSP2, EPHA2, GJA3, GJA8, LIM2, MIP, and TDRD7 represented in human cataract patients. Full article

(This article belongs to the Special Issue New Advances in Lens Biology and Pathology)

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19 pages, 1416 KiB

Open AccessEditor’s ChoiceReview

A Linkage between Angiogenesis and Inflammation in Neovascular Age-Related Macular Degeneration

by Hanna Heloterä and Kai Kaarniranta

Cells 2022, 11(21), 3453; https://doi.org/10.3390/cells11213453 - 1 Nov 2022

Cited by 56 | Viewed by 7747

Abstract

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with a limited understanding of its pathogenesis and the number of patients are all the time increasing. AMD is classified into two main forms: dry and neovascular AMD [...] Read more.

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with a limited understanding of its pathogenesis and the number of patients are all the time increasing. AMD is classified into two main forms: dry and neovascular AMD (nAMD). Dry AMD is the most prevalent form (80–90%) of AMD cases. Neovascular AMD (10–20% of AMD cases) is treated with monthly or more sparsely given intravitreal anti-vascular endothelial growth factor inhibitors, but unfortunately, not all patients respond to the current treatments. A clinical hallmark of nAMD is choroidal neovascularization. The progression of AMD is initially characterized by atrophic alterations in the retinal pigment epithelium, as well as the formation of lysosomal lipofuscin and extracellular drusen deposits. Cellular damage caused by chronic oxidative stress, protein aggregation and inflammatory processes may lead to advanced geographic atrophy and/or choroidal neovascularization and fibrosis. Currently, it is not fully known why different AMD phenotypes develop. In this review, we connect angiogenesis and inflammatory regulators in the development of nAMD and discuss therapy challenges and hopes. Full article

(This article belongs to the Special Issue The Role of Inflammation in AMD (Multifactorial Age-Related Macular Degeneration))

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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 26 | Viewed by 5519

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 6 | Viewed by 3307

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, 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 16 | Viewed by 3926

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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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 14 | Viewed by 2986

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 17 | Viewed by 7710

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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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 4318

Abstract

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

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

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

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17 pages, 1724 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 95 | Viewed by 11770

Abstract

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

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

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

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20 pages, 1610 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 19 | Viewed by 5297

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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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 28 | Viewed by 9429

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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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 35 | Viewed by 6027

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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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 56 | Viewed by 13331

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 34 | Viewed by 7275

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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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 7 | Viewed by 3551

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)

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 5228

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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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 120 | Viewed by 13450

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 49 | Viewed by 9741

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 27 | Viewed by 7001

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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