CellsPub Date : 2024-11-19DOI: 10.3390/cells13221913
Darshini Desai, Taejeong Song, Rohit R Singh, Akhil Baby, James McNamara, Lisa C Green, Pooneh Nabavizadeh, Mark Ericksen, Sholeh Bazrafshan, Sankar Natesan, Sakthivel Sadayappan
{"title":"<i>MYBPC3</i> D389V Variant Induces Hypercontractility in Cardiac Organoids.","authors":"Darshini Desai, Taejeong Song, Rohit R Singh, Akhil Baby, James McNamara, Lisa C Green, Pooneh Nabavizadeh, Mark Ericksen, Sholeh Bazrafshan, Sankar Natesan, Sakthivel Sadayappan","doi":"10.3390/cells13221913","DOIUrl":"https://doi.org/10.3390/cells13221913","url":null,"abstract":"<p><p><i>MYBPC3</i>, encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in <i>MYBPC3</i> by using isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs). The hiPSC-derived cardiomyocytes (hiPSC-CMs) and hCOs were generated from human subjects to define the molecular, cellular, functional, and energetic changes caused by the <i>MYBPC3</i><sup>D389V</sup> variant, which is associated with increased fractional shortening and highly prevalent in South Asian descendants. Recombinant C0-C2, N' region of cMyBP-C (wild-type and D389V), and myosin S2 proteins were also utilized to perform binding and motility assays in vitro. Confocal and electron microscopic analyses of hCOs generated from noncarriers (NC) and carriers of the <i>MYBPC3</i><sup>D389V</sup> variant revealed the presence of highly organized sarcomeres. Furthermore, functional experiments showed hypercontractility, faster calcium cycling, and faster contractile kinetics in hCOs expressing <i>MYBPC3</i><sup>D389V</sup> than NC hCOs. Interestingly, significantly increased cMyBP-C phosphorylation in <i>MYBPC3</i><sup>D389V</sup> hCOs was observed, but without changes in total protein levels, in addition to higher oxidative stress and lower mitochondrial membrane potential (ΔΨm). Next, spatial mapping revealed the presence of endothelial cells, fibroblasts, macrophages, immune cells, and cardiomyocytes in the hCOs. The hypercontractile function was significantly improved after the treatment of the myosin inhibitor mavacamten (CAMZYOS<sup>®</sup>) in <i>MYBPC3</i><sup>D389V</sup> hCOs. Lastly, various vitro binding assays revealed a significant loss of affinity in the presence of <i>MYBPC3</i><sup>D389V</sup> with myosin S2 region as a likely mechanism for hypercontraction. Conceptually, we showed the feasibility of assessing the functional and molecular mechanisms of HCM using highly translatable hCOs through pragmatic experiments that led to determining the <i>MYBPC3</i><sup>D389V</sup> hypercontractile phenotype, which was rescued by the administration of a myosin inhibitor.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dissecting the Impact of Genetic Background on Oncogenic Response to Radiation Exposure in the <i>Ptch1</i><sup>+/-</sup> Mouse Model.","authors":"Barbara Tanno, Emiliano Fratini, Simona Leonardi, Flavia Novelli, Valentina Pisano, Mariateresa Mancuso, Simonetta Pazzaglia","doi":"10.3390/cells13221912","DOIUrl":"https://doi.org/10.3390/cells13221912","url":null,"abstract":"<p><p>Medulloblastoma (MB) is a common primary brain cancer in children. The sonic hedgehog (SHH) pathway is indispensable for the normal development of the cerebellum, and MB is often caused by persistent SHH activation owing to mutations in pathway components. Patched1 (<i>PTCH1</i>) is the primary receptor for the SHH ligand and a negative regulator of the SHH signal transduction pathway. Mice heterozygous for the <i>Ptch1</i> gene (<i>Ptch1</i><sup>+/-</sup>) are predisposed to MB development. Irradiation of newborn <i>Ptch1</i><sup>+/-</sup> mice dramatically increases MB occurrence. A genetic background carrying the <i>Ptch1</i> mutation significantly influences the risk of developing MB. This study aims to investigate the genetic background-related mechanisms that regulate radiation-induced cellular response and oncogenesis in the cerebellum. We employed multiple approaches, including: (a) analysis of cellular radiosensitivity in granule cell precursors (GCPs), the MB cells of origin, derived from <i>Ptch1</i> mice with a genetic background that is sensitive (CD1) or resistant (C57Bl/6) to the induction of radiogenic MB; (b) identification of genes differentially expressed in spontaneous and radiation-induced MBs from these two mouse strains; (c) bioinformatic analysis to correlate the expression of radiation-induced genes with survival in MB patients; and (d) examining the expression of these genes in ex vivo MBs induced by single or repeated radiation doses. We have identified a potential gene expression signature-<i>Trp53bp1</i>, <i>Bax</i>, <i>Cyclin D1</i>, <i>p21</i>, and <i>Nanog</i>-that influences tumor response. In ex vivo cultured spontaneous MBs, the expression levels of these genes increase after irradiation in CD1 mice, but not in mice with a C57Bl/6 genetic background, suggesting that this signature could predict tumor response to radiation therapy and help develop strategies for targeting DNA damage repair in tumors. A detailed understanding of the mechanisms behind genetic background-related susceptibility to radiation-induced oncogenic responses is crucial for translational research.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-11-19DOI: 10.3390/cells13221920
Min-Koo Park, Jinhyun Ahn, Jin-Muk Lim, Minsoo Han, Ji-Won Lee, Jeong-Chan Lee, Sung-Joo Hwang, Keun-Cheol Kim
{"title":"A Transcriptomics-Based Machine Learning Model Discriminating Mild Cognitive Impairment and the Prediction of Conversion to Alzheimer's Disease.","authors":"Min-Koo Park, Jinhyun Ahn, Jin-Muk Lim, Minsoo Han, Ji-Won Lee, Jeong-Chan Lee, Sung-Joo Hwang, Keun-Cheol Kim","doi":"10.3390/cells13221920","DOIUrl":"https://doi.org/10.3390/cells13221920","url":null,"abstract":"<p><p>The clinical spectrum of Alzheimer's disease (AD) ranges dynamically from asymptomatic and mild cognitive impairment (MCI) to mild, moderate, or severe AD. Although a few disease-modifying treatments, such as lecanemab and donanemab, have been developed, current therapies can only delay disease progression rather than halt it entirely. Therefore, the early detection of MCI and the identification of MCI patients at high risk of progression to AD remain urgent unmet needs in the super-aged era. This study utilized transcriptomics data from cognitively unimpaired (CU) individuals, MCI, and AD patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and leveraged machine learning models to identify biomarkers that differentiate MCI from CU and also distinguish AD from MCI individuals. Furthermore, Cox proportional hazards analysis was conducted to identify biomarkers predictive of the progression from MCI to AD. Our machine learning models identified a unique set of gene expression profiles capable of achieving an area under the curve (AUC) of 0.98 in distinguishing those with MCI from CU individuals. A subset of these biomarkers was also found to be significantly associated with the risk of progression from MCI to AD. A linear mixed model demonstrated that plasma tau phosphorylated at threonine 181 (pTau181) and neurofilament light chain (NFL) exhibit the prognostic value in predicting cognitive decline longitudinally. These findings underscore the potential of integrating machine learning (ML) with transcriptomic profiling in the early detection and prognostication of AD. This integrated approach could facilitate the development of novel diagnostic tools and therapeutic strategies aimed at delaying or preventing the onset of AD in at-risk individuals. Future studies should focus on validating these biomarkers in larger, independent cohorts and further investigating their roles in AD pathogenesis.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-11-19DOI: 10.3390/cells13221921
Ekaterina Tyrina, Danila Yakubets, Elena Markina, Ludmila Buravkova
{"title":"Hippo Signaling Pathway Involvement in Osteopotential Regulation of Murine Bone Marrow Cells Under Simulated Microgravity.","authors":"Ekaterina Tyrina, Danila Yakubets, Elena Markina, Ludmila Buravkova","doi":"10.3390/cells13221921","DOIUrl":"https://doi.org/10.3390/cells13221921","url":null,"abstract":"<p><p>The development of osteopenia is one of the most noticeable manifestations of the adverse effects of space factors on crew members. The Hippo signaling pathway has been shown to play a central role in regulating the functional activity of cells through their response to mechanical stimuli. In the present study, the components of the Hippo pathway and the protective properties of osteodifferentiation inducers were investigated under simulated microgravity (smg) using a heterotypic bone marrow cell culture model, which allows for the maintenance of the close interaction between the stromal and hematopoietic compartments, present in vivo and of great importance for both the fate of osteoprogenitors and hematopoiesis. After 14 days of smg, the osteopotential and osteodifferentiation of bone marrow stromal progenitor cells, the expression of Hippo cascade genes and the immunocytochemical status of the adherent fraction of bone marrow cells, as well as the paracrine profile in the conditioned medium and the localization of Yap1 and Runx2 in mechanosensitive cells of the bone marrow were obtained. Simulated microgravity negatively affects stromal and hematopoietic cells when interacting in a heterotypic murine bone marrow cell culture. This is evidenced by the decrease in cell proliferation and osteopotential. Changes in the production of pleiotropic cytokines IL-6, GROβ and MCP-1 were revealed. Fourteen days of simulated microgravity induced a decrease in the nuclear translocation of Yap1 and the transcription factor Runx2 in the stromal cells of the intact group. Exposure to osteogenic induction conditions partially compensated for the negative effect of simulated microgravity. The data obtained will be crucial for understanding the effects of spaceflight on osteoprogenitor cell growth and differentiation via Hippo-Yap signaling.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-11-19DOI: 10.3390/cells13221911
Judith A W Westerhuis, Jeroen Dudink, Bente E C A Wijnands, Chris I De Zeeuw, Cathrin B Canto
{"title":"Impact of Intrauterine Insults on Fetal and Postnatal Cerebellar Development in Humans and Rodents.","authors":"Judith A W Westerhuis, Jeroen Dudink, Bente E C A Wijnands, Chris I De Zeeuw, Cathrin B Canto","doi":"10.3390/cells13221911","DOIUrl":"https://doi.org/10.3390/cells13221911","url":null,"abstract":"<p><p>Many children suffer from neurodevelopmental aberrations that have long-term effects. To understand the consequences of pathological processes during particular periods in neurodevelopment, one has to understand the differences in the developmental timelines of brain regions. The cerebellum is one of the first brain structures to differentiate during development but one of the last to achieve maturity. This relatively long period of development underscores its vulnerability to detrimental environmental exposures throughout gestation. Moreover, as postnatal functionality of the cerebellum is multifaceted, enveloping sensorimotor, cognitive, and emotional domains, prenatal disruptions in cerebellar development can result in a large variety of neurological and mental health disorders. Here, we review major intrauterine insults that affect cerebellar development in both humans and rodents, ranging from abuse of toxic chemical agents, such as alcohol, nicotine, cannabis, and opioids, to stress, malnutrition, and infections. Understanding these pathological mechanisms in the context of the different stages of cerebellar development in humans and rodents can help us to identify critical and vulnerable periods and thereby prevent the risk of associated prenatal and early postnatal damage that can lead to lifelong neurological and cognitive disabilities. The aim of the review is to raise awareness and to provide information for obstetricians and other healthcare professionals to eventually design strategies for preventing or rescuing related neurodevelopmental disorders.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-11-19DOI: 10.3390/cells13221909
Kostas A Papavassiliou, Amalia A Sofianidi, Vassiliki A Gogou, Athanasios G Papavassiliou
{"title":"The Clinical Significance of Cancer-Associated Fibroblasts Classification in Non-Small Cell Lung Cancer.","authors":"Kostas A Papavassiliou, Amalia A Sofianidi, Vassiliki A Gogou, Athanasios G Papavassiliou","doi":"10.3390/cells13221909","DOIUrl":"https://doi.org/10.3390/cells13221909","url":null,"abstract":"<p><p>Malignant cells flourish within a specialized environment known as the tumor microenvironment (TME) [...].</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-11-19DOI: 10.3390/cells13221914
Jordan Carroll, Jessie Chen, Rahul Mittal, Joana R N Lemos, Mannat Mittal, Shreya Juneja, Amro Assayed, Khemraj Hirani
{"title":"Decoding the Significance of Alpha Cell Function in the Pathophysiology of Type 1 Diabetes.","authors":"Jordan Carroll, Jessie Chen, Rahul Mittal, Joana R N Lemos, Mannat Mittal, Shreya Juneja, Amro Assayed, Khemraj Hirani","doi":"10.3390/cells13221914","DOIUrl":"https://doi.org/10.3390/cells13221914","url":null,"abstract":"<p><p>Alpha cells in the pancreas, traditionally known for their role in secreting glucagon to regulate blood glucose levels, are gaining recognition for their involvement in the pathophysiology of type 1 diabetes (T1D). In T1D, autoimmune destruction of beta cells results in insulin deficiency, which in turn may dysregulate alpha cell function, leading to elevated glucagon levels and impaired glucose homeostasis. This dysfunction is characterized by inappropriate glucagon secretion, augmenting the risk of life-threatening hypoglycemia. Moreover, insulin deficiency and autoimmunity alter alpha cell physiological responses, further exacerbating T1D pathophysiology. Recent studies suggest that alpha cells undergo transdifferentiation and interact with beta cells through mechanisms involving gamma-aminobutyric acid (GABA) signaling. Despite these advances, the exact pathways and interactions remain poorly understood and are often debated. Understanding the precise role of alpha cells in T1D is crucial, as it opens up avenues for developing new therapeutic strategies for T1D. Potential strategies include targeting alpha cells to normalize glucagon secretion, utilizing glucagon receptor antagonists, enhancing GABA signaling, and employing glucagon-like peptide-1 (GLP-1) receptor agonists. These approaches aim to improve glycemic control and reduce the risk of hypoglycemic events in individuals with T1D. This review provides an overview of alpha cell function in T1D, highlighting the emerging focus on alpha cell dysfunction in the context of historically well-developed beta cell research.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"LUCAT1-Mediated Competing Endogenous RNA (ceRNA) Network in Triple-Negative Breast Cancer.","authors":"Deepak Verma, Sumit Siddharth, Ashutosh S Yende, Qitong Wu, Dipali Sharma","doi":"10.3390/cells13221918","DOIUrl":"https://doi.org/10.3390/cells13221918","url":null,"abstract":"<p><p>Breast cancer is a heterogeneous disease comprising multiple molecularly distinct subtypes with varied prevalence, prognostics, and treatment strategies. Among them, triple-negative breast cancer, though the least prevalent, is the most aggressive subtype, with limited therapeutic options. Recent emergence of competing endogenous RNA (ceRNA) networks has highlighted how long noncoding RNAs (lncRNAs), microRNAs (miRs), and mRNA orchestrate a complex interplay meticulously modulating mRNA functionality. Focusing on TNBC, this study aimed to construct a ceRNA network using differentially expressed lncRNAs, miRs, and mRNAs. We queried the differentially expressed lncRNAs (DElncRNAs) between TNBC and luminal samples and found 389 upregulated and 386 downregulated lncRNAs, including novel transcripts in TNBC. DElncRNAs were further evaluated for their clinical, functional, and mechanistic relevance to TNBCs using the lnc2cancer 3.0 database, which presented LUCAT1 (lung cancer-associated transcript 1) as a putative node. Next, the ceRNA network (lncRNA-miRNA-mRNA) of LUCAT1 was established. Several miRNA-mRNA connections of LUCAT1 implicated in regulating stemness (LUCAT1-miR-375-Yap1, LUCAT1-miR181-5p-Wnt, LUCAT1-miR-199a-5p-ZEB1), apoptosis (LUCAT1-miR-181c-5p-Bcl2), drug efflux (LUCAT1-miR-200c-ABCB1, LRP1, MRP5, MDR1), and sheddase activities (LUCAT1-miR-493-5p-ADAM10) were identified, indicating an intricate regulatory mechanism of LUCAT1 in TNBC. Indeed, LUCAT1 silencing led to mitigated cell growth, migration, and stem-like features in TNBC. This work sheds light on the LUCAT1 ceRNA network in TNBC and implies its involvement in TNBC growth and progression.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-11-18DOI: 10.3390/cells13221899
Gregory Livshits, Alexander Kalinkovich
{"title":"Resolution of Chronic Inflammation, Restoration of Epigenetic Disturbances and Correction of Dysbiosis as an Adjunctive Approach to the Treatment of Atopic Dermatitis.","authors":"Gregory Livshits, Alexander Kalinkovich","doi":"10.3390/cells13221899","DOIUrl":"https://doi.org/10.3390/cells13221899","url":null,"abstract":"<p><p>Atopic dermatitis (AD) is a chronic inflammatory skin disease with multifactorial and unclear pathogenesis. Its development is characterized by two key elements: epigenetic dysregulation of molecular pathways involved in AD pathogenesis and disrupted skin and gut microbiota (dysbiosis) that jointly trigger and maintain chronic inflammation, a core AD characteristic. Current data suggest that failed inflammation resolution is the main pathogenic mechanism underlying AD development. Inflammation resolution is provided by specialized pro-resolving mediators (SPMs) derived from dietary polyunsaturated fatty acids acting through cognate receptors. SPM levels are reduced in AD patients. Administration of SPMs or their stable, small-molecule mimetics and receptor agonists, as well as supplementation with probiotics/prebiotics, demonstrate beneficial effects in AD animal models. Epidrugs, compounds capable of restoring disrupted epigenetic mechanisms associated with the disease, improve impaired skin barrier function in AD models. Based on these findings, we propose a novel, multilevel AD treatment strategy aimed at resolving chronic inflammation by application of SPM mimetics and receptor agonists, probiotics/prebiotics, and epi-drugs. This approach can be used in conjunction with current AD therapy, resulting in AD alleviation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-11-18DOI: 10.3390/cells13221905
Da-Long Dong, Guang-Zhen Jin
{"title":"YAP and ECM Stiffness: Key Drivers of Adipocyte Differentiation and Lipid Accumulation.","authors":"Da-Long Dong, Guang-Zhen Jin","doi":"10.3390/cells13221905","DOIUrl":"https://doi.org/10.3390/cells13221905","url":null,"abstract":"<p><p>ECM stiffness significantly influences the differentiation of adipose-derived stem cells (ADSCs), with YAP-a key transcription factor in the Hippo signaling pathway-playing a pivotal role. This study investigates the effects of ECM stiffness on ADSC differentiation and its relationship with YAP signaling. Various hydrogel concentrations were employed to simulate different levels of ECM stiffness, and their impact on ADSC differentiation was assessed through material properties, adipocyte-specific gene expression, lipid droplet staining, YAP localization, and protein levels. Our results demonstrated that increasing hydrogel stiffness enhanced adipocyte differentiation in a gradient manner. Notably, inhibiting YAP signaling further increased lipid droplet accumulation, suggesting that ECM stiffness influences adipogenesis by modulating YAP signaling and its cytoplasmic phosphorylation. This study elucidates the molecular mechanisms underlying ECM stiffness-dependent lipid deposition, highlighting YAP's regulatory role in adipogenesis. These findings provide valuable insights into the regulation of cell differentiation and have important implications for tissue engineering and obesity treatment strategies.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 22","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}