Matrix Biology最新文献

{"title":"SERPINA3 is a marker of cartilage differentiation and is essential for the expression of extracellular matrix genes during early chondrogenesis","authors":"Matthew J Barter ,&nbsp;David A Turner ,&nbsp;Sarah J Rice ,&nbsp;Mary Hines ,&nbsp;Hua Lin ,&nbsp;Adrian M.D. Falconer ,&nbsp;Euan McDonnell ,&nbsp;Jamie Soul ,&nbsp;Maria del Carmen Arques ,&nbsp;G Nicholas Europe-Finner ,&nbsp;Andrew D. Rowan ,&nbsp;David A. Young ,&nbsp;David J. Wilkinson","doi":"10.1016/j.matbio.2024.07.004","DOIUrl":"10.1016/j.matbio.2024.07.004","url":null,"abstract":"<div><p>Serine proteinase inhibitors (serpins) are a family of structurally similar proteins which regulate many diverse biological processes from blood coagulation to extracellular matrix (ECM) remodelling. Chondrogenesis involves the condensation and differentiation of mesenchymal stem cells (MSCs) into chondrocytes which occurs during early development. Here, and for the first time, we demonstrate that one serpin, SERPINA3 (gene name <em>SERPINA3,</em> protein also known as alpha-1 antichymotrypsin), plays a critical role in chondrogenic differentiation. We observed that <em>SERPINA3</em> expression was markedly induced at early time points during <em>in vitro</em> chondrogenesis. We examined the expression of <em>SERPINA3</em> in human cartilage development, identifying significant enrichment of <em>SERPINA3</em> in developing cartilage compared to total limb, which correlated with well-described markers of cartilage differentiation. When <em>SERPINA3</em> was silenced using siRNA, cartilage pellets were smaller and contained lower proteoglycan as determined by dimethyl methylene blue assay (DMMB) and safranin-O staining. Consistent with this, RNA sequencing revealed significant downregulation of genes associated with cartilage ECM formation perturbing chondrogenesis. Conversely, <em>SERPINA3</em> silencing had a negligible effect on the gene expression profile during osteogenesis suggesting the role of SERPINA3 is specific to chondrocyte differentiation. The global effect on cartilage formation led us to investigate the effect of <em>SERPINA3</em> silencing on the master transcriptional regulator of chondrogenesis, SOX9. Indeed, we observed that SOX9 protein levels were markedly reduced at early time points suggesting a role for SERPINA3 in regulating SOX9 expression and activity. In summary, our data support a non-redundant role for SERPINA3 in enabling chondrogenesis via regulation of SOX9 levels.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 33-42"},"PeriodicalIF":4.5,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000957/pdfft?md5=0eaeee488a472aa9c27aae6f1154e131&pid=1-s2.0-S0945053X24000957-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141890715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matricellular protein CCN1 promotes collagen alignment and scar integrity after myocardial infarction","authors":"Annalara G. Fischer ,&nbsp;Erin M. Elliott ,&nbsp;Kenneth R. Brittian ,&nbsp;Lauren Garrett ,&nbsp;Ghazal Sadri ,&nbsp;Julia Aebersold ,&nbsp;Richa A. Singhal ,&nbsp;Yibing Nong ,&nbsp;Andrew Leask ,&nbsp;Steven P. Jones ,&nbsp;Joseph B. Moore IV","doi":"10.1016/j.matbio.2024.08.001","DOIUrl":"10.1016/j.matbio.2024.08.001","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Members of the cellular communication network family (CCN) of matricellular proteins, like CCN1, have long been implicated in the regulation of cellular processes underlying wound healing, tissue fibrogenesis, and collagen dynamics. While many studies suggest antifibrotic actions for CCN1 in the adult heart through the promotion of myofibroblast senescence, they largely relied on exogenous supplementation strategies in &lt;em&gt;in vivo&lt;/em&gt; models of cardiac injury where its expression is already induced—which may confound interpretation of its function in this process. The objective of this study was to interrogate the role of the endogenous protein on fibroblast function, collagen structural dynamics, and its associated impact on cardiac fibrosis after myocardial infarction (MI).&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods/results&lt;/h3&gt;&lt;p&gt;Here, we employed CCN1 loss-of-function methodologies, including both &lt;em&gt;in vitro&lt;/em&gt; siRNA-mediated depletion and &lt;em&gt;in vivo&lt;/em&gt; fibroblast-specific knockout mice to assess the role of the endogenous protein on cardiac fibroblast fibrotic signaling, and its involvement in acute scar formation after MI. &lt;em&gt;In vitro&lt;/em&gt; depletion of CCN1 reduced cardiac fibroblast senescence and proliferation. Although depletion of CCN1 decreased the expression of collagen processing and stabilization enzymes (&lt;em&gt;i.e.&lt;/em&gt;, P4HA1, PLOD1, and PLOD2), it did not inhibit myofibroblast induction or type I collagen synthesis. Alone, fibroblast-specific removal of CCN1 did not negatively impact ventricular performance or myocardial collagen content but did contribute to disorganization of collagen fibrils and increased matrix compliance. Similarly, &lt;em&gt;Ccn1&lt;/em&gt; ablated animals subjected to MI showed no discernible alterations in cardiac structure or function one week after permanent coronary artery ligation, but exhibited marked increases in incidence of mortality and cardiac rupture. Consistent with our findings that CCN1 depletion does not assuage myofibroblast conversion or type I collagen synthesis &lt;em&gt;in vitro, Ccn1&lt;/em&gt; knockout animals revealed no measurable differences in collagen scar width or mass compared to controls; however, detailed structural analyses via SHG and TEM of scar regions revealed marked alterations in their scar collagen topography—exhibiting changes in numerous macro- and micro-level collagen architectural attributes. Specifically, &lt;em&gt;Ccn1&lt;/em&gt; knockout mice displayed heightened ECM structural complexity in post-MI scar regions, including diminished local alignment and heightened tortuosity of collagen fibers, as well as reduced organizational coherency, packing, and size of collagen fibrils. Associated with these changes in ECM topography with the loss of CCN1 were reductions in fibroblast-matrix interactions, as evidenced by reduced fibroblast nuclear and cellular deformation &lt;em&gt;in vivo&lt;/em&gt; and reduced focal-adhesion formation &lt;em&gt;in vitro&lt;/em&gt;; findings that ultimately suggest CCN1’s abili","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 14-32"},"PeriodicalIF":4.5,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141890714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic control of collagen synthesis","authors":"Julien Guillard ,&nbsp;Simon Schwörer","doi":"10.1016/j.matbio.2024.07.003","DOIUrl":"10.1016/j.matbio.2024.07.003","url":null,"abstract":"<div><p>The extracellular matrix (ECM) is present in all tissues and crucial in maintaining normal tissue homeostasis and function. Defects in ECM synthesis and remodeling can lead to various diseases, while overproduction of ECM components can cause severe conditions like organ fibrosis and influence cancer progression and therapy resistance. Collagens are the most abundant core ECM proteins in physiological and pathological conditions and are predominantly synthesized by fibroblasts. Previous efforts to target aberrant collagen synthesis in fibroblasts by inhibiting pro-fibrotic signaling cascades have been ineffective. More recently, metabolic rewiring downstream of pro-fibrotic signaling has emerged as a critical regulator of collagen synthesis in fibroblasts. Here, we propose that targeting the metabolic pathways involved in ECM biomass generation provides a novel avenue for treating conditions characterized by excessive collagen accumulation. This review summarizes the unique metabolic challenges collagen synthesis imposes on fibroblasts and discusses how underlying metabolic networks could be exploited to create therapeutic opportunities in cancer and fibrotic disease. Finally, we provide a perspective on open questions in the field and how conceptual and technical advances will help address them to unlock novel metabolic vulnerabilities of collagen synthesis in fibroblasts and beyond.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 43-56"},"PeriodicalIF":4.5,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of OGN in lung myofibroblasts attenuates pulmonary fibrosis by inhibiting integrin αv-mediated TGF-β/Smad pathway activation","authors":"Shaojie Huang ,&nbsp;Yingying Lin ,&nbsp;Qiwen Deng ,&nbsp;Yuanjia Zhang ,&nbsp;Senyi Peng ,&nbsp;Yuan Qiu ,&nbsp;Wenqi Huang ,&nbsp;Zhongxing Wang ,&nbsp;Xiaofan Lai","doi":"10.1016/j.matbio.2024.07.001","DOIUrl":"10.1016/j.matbio.2024.07.001","url":null,"abstract":"<div><h3>Background</h3><p>Idiopathic pulmonary fibrosis (IPF) represents a severe and progressive manifestation of idiopathic interstitial pneumonia marked by an uncertain etiology along with an unfavorable prognosis. Osteoglycin (OGN), belonging to the small leucine-rich proteoglycans family, assumes pivotal functions in both tissue formation and damage response. However, the roles and potential mechanisms of OGN in the context of lung fibrosis remain unexplored.</p></div><div><h3>Methods</h3><p>The assessment of OGN expression levels in fibrotic lungs was conducted across various experimental lung fibrosis mouse models. To elucidate the effects of OGN on the differentiation of lung myofibroblasts, both OGN knockdown and OGN overexpression were employed in vitro. The expression of integrin αv, along with its colocalization with lysosomes and latency-associated peptide (LAP), was monitored in OGN-knockdown lung myofibroblasts. Furthermore, the role of OGN in lung fibrosis was investigated through OGN knockdown utilizing adeno-related virus serotype 6 (AAV6)-mediated delivery.</p></div><div><h3>Results</h3><p>OGN exhibited upregulation in both lungs and myofibroblasts across diverse lung fibrosis mouse models. And laboratory experiments in vitro demonstrated that OGN knockdown inhibited the TGF-β/Smad signaling pathway in lung myofibroblasts. Conversely, OGN overexpression promoted TGF-β/Smad pathway in these cells. Mechanistic insights revealed that OGN knockdown facilitated lysosome-mediated degradation of integrin αv while inhibiting its binding to latency-associated peptide (LAP). Remarkably, AAV6-targeted OGN knockdown ameliorated the extent of lung fibrosis in experimental mouse models.</p></div><div><h3>Conclusion</h3><p>Our results indicate that inhibiting OGN signaling could serve as a promising therapeutic way for lung fibrosis.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 87-97"},"PeriodicalIF":4.5,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000921/pdfft?md5=9880034d0cc3b8225e8672728061e556&pid=1-s2.0-S0945053X24000921-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141635543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial DNA mutations attenuate Bleomycin-induced dermal fibrosis by inhibiting differentiation into myofibroblasts","authors":"Lena Reiter ,&nbsp;Nadine Niehoff ,&nbsp;Daniela Weiland ,&nbsp;Doris Helbig ,&nbsp;Sabine A. Eming ,&nbsp;Thomas Krieg ,&nbsp;Julia Etich ,&nbsp;Bent Brachvogel ,&nbsp;Rudolf J. Wiesner ,&nbsp;Jana Knuever","doi":"10.1016/j.matbio.2024.07.002","DOIUrl":"10.1016/j.matbio.2024.07.002","url":null,"abstract":"<div><p>Post-mitotic, non-proliferative dermal fibroblasts have crucial functions in maintenance and restoration of tissue homeostasis. They are involved in essential processes such as wound healing, pigmentation and hair growth, but also tumor development and aging-associated diseases. These processes are energetically highly demanding and error prone when mitochondrial damage occurs. However, mitochondrial function in fibroblasts and the influence of mitochondrial dysfunction on fibroblast-specific demands are still unclear. To address these questions, we created a mouse model in which accelerated cell-specific mitochondrial DNA (mtDNA) damage accumulates. We crossed mice carrying a dominant-negative mutant of the mitochondrial replicative helicase Twinkle (RosaSTOP system) with mice that express fibroblast-specific Cre Recombinase (Collagen1A2 Cre^ERT) which can be activated by Tamoxifen (Twinkle^FIBRO). Thus, we are able to induce mtDNA deletions and duplications in specific cells, a process which resembles the physiological aging process in humans, where this damage accumulates in all tissues. Upon proliferation <em>in vitro</em>, Tamoxifen induced Twinkle fibroblasts deplete most of their mitochondrial DNA which, although not disturbing the stoichiometry of the respiratory chain complexes, leads to reduced ROS production and mitochondrial membrane potential as well as an anti-inflammatory and anti-fibrotic profile of the cells. In Sodium Azide treated wildtype fibroblasts, without a functioning respiratory chain, we observe the opposite, a rather pro-inflammatory and pro-fibrotic signature. Upon accumulation of mitochondrial DNA mutations <em>in vivo</em> the Twinkle^FIBRO mice are protected from fibrosis development induced by intradermal Bleomycin injections. This is due to dampened differentiation of the dermal fibroblasts into α−smooth-muscle-actin positive myofibroblasts in Twinkle^FIBRO mice. We thus provide evidence for striking differences of the impact that mtDNA mutations have in contrast to blunted mitochondrial function in dermal fibroblasts and skin homeostasis. These data contribute to improved understanding of mitochondrial function and dysfunction in skin and provide mechanistic insight into potential targets to treat skin fibrosis in the future.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 72-86"},"PeriodicalIF":4.5,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000933/pdfft?md5=0f0631efe84cae0e3ad160e0f43f5cfc&pid=1-s2.0-S0945053X24000933-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-1α inhibits transforming growth factor-β1 and β2-induced extracellular matrix production, remodeling and signaling in human lung fibroblasts: Master regulator in lung mucosal repair","authors":"Kauna Usman ,&nbsp;May Fouadi ,&nbsp;Kingsley Okechukwu Nwozor ,&nbsp;Fatemeh Aminazadeh ,&nbsp;Parameswaran Nair ,&nbsp;Honglin Luo ,&nbsp;Don D. Sin ,&nbsp;Emmanuel Twumasi Osei ,&nbsp;Tillie-Louise Hackett","doi":"10.1016/j.matbio.2024.06.007","DOIUrl":"https://doi.org/10.1016/j.matbio.2024.06.007","url":null,"abstract":"<div><h3>Background</h3><p>Lung fibroblasts play a central role in maintaining lung homeostasis and facilitating repair through the synthesis and organization of the extracellular matrix (ECM). This study investigated the cross-talk between interleukin-1 alpha (IL-1α) and transforming growth factor-β (TGF-β) signaling, two key regulators in tissue repair and fibrosis, in the context of lung fibroblast repair in the healthy lung.</p></div><div><h3>Results</h3><p>Stimulation of lung fibroblasts with TGF-β1 and TGF-β2 induced collagen-I and fibronectin protein expression (<em>p</em> &lt; 0.05), a response inhibited with co-treatment with IL-1α (<em>p</em> &lt; 0.05). Additionally, TGF-β1 and TGF-β2 induced myofibroblast differentiation, and collagen-I gel contraction, which were both suppressed by IL-1α (<em>p</em> &lt; 0.05). In contrast, interleukin (IL)-6, IL-8 and thymic stromal lymphopoietin induced by IL-1α, were unaffected by TGF-β1 or TGF-β2. Mechanistically, IL-1α administration led to the suppression of TGF-β1 and TGF-β2 signaling, through downregulation of mRNA and protein for TGF-β receptor II and the downstream adaptor protein TRAF6, but not through miR-146a that is known to be induced by IL-1α.</p></div><div><h3>Discussion</h3><p>IL-1α acts as a master regulator, modulating TGF-β1 and TGF-β2-induced ECM production, remodeling, and myofibroblast differentiation in human lung fibroblasts, playing a vital role in balancing tissue repair versus fibrosis. Further research is required to understand the dysregulated cross-talk between IL-1α and TGF-β signaling in chronic lung diseases and the exploration of therapeutic opportunities.</p></div><div><h3>Methods</h3><p>Primary human lung fibroblasts (PHLF) were treated with media control, or 1 ng/ml IL-1α with or without 50 ng/ml TGF-β1 or TGF-β2 for 1, 6 and 72 h. Cell lysates were assessed for the expression of ECM proteins and signaling molecules by western blot, miRNA by qPCR, mRNA by RNA sequencing and cell supernatants for cytokine production by ELISA. PHLFs were also seeded in non-tethered collagen-I gels to measure contraction, and myofibroblast differentiation using confocal microscopy.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 47-58"},"PeriodicalIF":4.5,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X2400091X/pdfft?md5=d93cb3b548e4e61901e2a96e8d3b8a66&pid=1-s2.0-S0945053X2400091X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141543175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of 3-O-sulfotransferase enzymes, Hs3st3a1 and Hs3st3b1, reduces kidney and glomerular size and disrupts glomerular architecture","authors":"","doi":"10.1016/j.matbio.2024.06.006","DOIUrl":"10.1016/j.matbio.2024.06.006","url":null,"abstract":"<div><p>Heparan sulfate (HS) is an important component of the kidney anionic filtration barrier, the glomerular basement membrane (GBM). HS chains attached to proteoglycan protein cores are modified by sulfotransferases in a highly ordered series of biosynthetic steps resulting in immense structural diversity due to negatively charged sulfate modifications. 3-<em>O</em>-sulfation is the least abundant modification generated by a family of seven isoforms but creates the most highly sulfated HS domains. We analyzed the kidney phenotypes in the <em>Hs3st3a1, Hs3st3b1</em> and <em>Hs3st6</em> -knockout (KO) mice, the isoforms enriched in kidney podocytes. Individual KO mice show no overt kidney phenotype, although <em>Hs3st3b1</em> kidneys were smaller than wildtype (WT). Furthermore, <em>Hs3st3a1^-/-; Hs3st3b1^-/-</em> double knockout (DKO) kidneys were smaller but also had a reduction in glomerular size relative to wildtype (WT). Mass spectrometry analysis of kidney HS showed reduced 3-<em>O</em>-sulfation in <em>Hs3st3a1^-/-</em> and <em>Hs3st3b1^-/-</em>, but not in <em>Hs3st6^-/-</em> kidneys. Glomerular HS showed reduced HS staining and reduced ligand-and-carbohydrate engagement (LACE) assay, a tool that detects changes in binding of growth factor receptor-ligand complexes to HS. Interestingly, DKO mice have increased levels of blood urea nitrogen, although no differences were detected in urinary levels of albumin, creatinine and nephrin. Finally, transmission electron microscopy showed irregular and thickened GBM and podocyte foot process effacement in the DKO compared to WT. Together, our data suggest that loss of 3-<em>O</em>-HS domains disrupts the kidney glomerular architecture without affecting the glomerular filtration barrier and overall kidney function.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"133 ","pages":"Pages 134-149"},"PeriodicalIF":4.5,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000908/pdfft?md5=086a230b39396661fb6dd8b43ec26ccb&pid=1-s2.0-S0945053X24000908-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-214–3p regulates Piezo1, lysyl oxidases and mitochondrial function in human cardiac fibroblasts","authors":"Christopher J. Trevelyan ,&nbsp;Amanda D.V. MacCannell ,&nbsp;Leander Stewart ,&nbsp;Theodora Tarousa ,&nbsp;Hannah A. Taylor ,&nbsp;Michael Murray ,&nbsp;Sumia A. Bageghni ,&nbsp;Karen E. Hemmings ,&nbsp;Mark J. Drinkhill ,&nbsp;Lee D. Roberts ,&nbsp;Andrew J. Smith ,&nbsp;Karen E. Porter ,&nbsp;Karen A. Forbes ,&nbsp;Neil A. Turner","doi":"10.1016/j.matbio.2024.06.005","DOIUrl":"10.1016/j.matbio.2024.06.005","url":null,"abstract":"<div><p>Cardiac fibroblasts are pivotal regulators of cardiac homeostasis and are essential in the repair of the heart after myocardial infarction (MI), but their function can also become dysregulated, leading to adverse cardiac remodelling involving both fibrosis and hypertrophy. MicroRNAs (miRNAs) are noncoding RNAs that target mRNAs to prevent their translation, with specific miRNAs showing differential expression and regulation in cardiovascular disease. Here, we show that miR-214–3p is enriched in the fibroblast fraction of the murine heart, and its levels are increased with cardiac remodelling associated with heart failure, or in the acute phase after experimental MI. Tandem mass tagging proteomics and in-silico network analyses were used to explore protein targets regulated by miR-214–3p in cultured human cardiac fibroblasts from multiple donors. Overexpression of miR-214–3p by miRNA mimics resulted in decreased expression and activity of the Piezo1 mechanosensitive cation channel, increased expression of the entire lysyl oxidase (LOX) family of collagen cross-linking enzymes, and decreased expression of an array of mitochondrial proteins, including mitofusin-2 (MFN2), resulting in mitochondrial dysfunction, as measured by citrate synthase and Seahorse mitochondrial respiration assays. Collectively, our data suggest that miR-214–3p is an important regulator of cardiac fibroblast phenotypes and functions key to cardiac remodelling, and that this miRNA represents a potential therapeutic target in cardiovascular disease.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 34-46"},"PeriodicalIF":4.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000891/pdfft?md5=dedfa241d4aff0fe56908d1113a212b1&pid=1-s2.0-S0945053X24000891-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated fibroblasts promote proliferation, angiogenesis, metastasis and immunosuppression in gastric cancer","authors":"Peiyuan Li,&nbsp;Huan Zhang,&nbsp;Tao Chen,&nbsp;Yajing Zhou,&nbsp;Jiaoyang Yang,&nbsp;Jin Zhou","doi":"10.1016/j.matbio.2024.06.004","DOIUrl":"10.1016/j.matbio.2024.06.004","url":null,"abstract":"<div><p>Despite advances in surgery, radiotherapy and immunotherapy, the mortality rate for gastric cancer remains one of the highest in the world. A large body of evidence has demonstrated that cancer-associated fibroblasts (CAFs), as core members of the stroma, can secrete cytokines, proteins and exosomes to create a tumour microenvironment that is conducive to cancer cell survival. CAFs can also interact with cancer cells to form a complex signalling network, enabling cancer cells to more easily metastasise to other organs and tissues in the body and develop metastatic foci. In this review, we provide an overview of the CAFs concept and activators. We focus on elucidating their effects on immune cells, intratumoural vasculature, extracellular matrix, as well as cancer cell activity, metastatic power and metabolism, and on enhancing the metastatic ability of cancer cells through activation of JAK/STAT, NF/κB and CXCL12/CXCR4. Various therapeutic agents targeting CAFs are also under development and are expected to improve the prognosis of gastric cancer in combination with existing treatment options.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 59-71"},"PeriodicalIF":4.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X2400088X/pdfft?md5=4f9e9676cb04f16a93eee54c9235018d&pid=1-s2.0-S0945053X2400088X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The fibroblast hormone Endotrophin is a biomarker of mortality in chronic diseases","authors":"Federica Genovese ,&nbsp;Cecilie Bager ,&nbsp;Peder Frederiksen ,&nbsp;Dario Vazquez ,&nbsp;Jannie Marie Bülow Sand ,&nbsp;R Gisli Jenkins ,&nbsp;Toby M. Maher ,&nbsp;Iain D. Stewart ,&nbsp;Philip L. Molyneaux ,&nbsp;William A Fahy ,&nbsp;Louise V. Wain ,&nbsp;Jørgen Vestbo ,&nbsp;Carmel Nanthakumar ,&nbsp;Saher Burhan Shaker ,&nbsp;Nils Hoyer ,&nbsp;Diana Julie Leeming ,&nbsp;Jacob George ,&nbsp;Jonel Trebicka ,&nbsp;Daniel Guldager Kring Rasmussen ,&nbsp;Michael K. Hansen ,&nbsp;Detlef Schuppan","doi":"10.1016/j.matbio.2024.06.003","DOIUrl":"10.1016/j.matbio.2024.06.003","url":null,"abstract":"<div><p>Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases.</p><p>We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PRO<img>C6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PRO<img>C6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available.</p><p>In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (<em>N</em> = 15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95 % CI 1.75—2.52) for a 2-fold increase in PRO<img>C6, with some heterogeneity observed between the studies (I²=70 %).</p><p>This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat.</p></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"132 ","pages":"Pages 1-9"},"PeriodicalIF":6.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0945053X24000854/pdfft?md5=9e4a241d5e9ff9bac7f93d4d7fd3e3a7&pid=1-s2.0-S0945053X24000854-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}