Pub Date : 2025-06-01Epub Date: 2025-04-03DOI: 10.1016/j.matbio.2025.04.001
Antonio Inforzato , Anthony J. Day
Pentraxin-3 (PTX3) is a secreted protein with roles in the stabilisation of hyaluronan-rich extracellular matrices involved in reproductive biology and inflammatory processes, as well as additional functions in innate immunity and cancer. Our recent structural studies (Shah et al., 2025; DOI:10.1016/j.matbio.2025.01.002), involving X-ray crystallography, cryo-electron microscopy (cryoEM) and AlphaFold modelling, have provided clues as to how PTX3 becomes assembled into an octamer from eight identical protomer subunits. Here it was proposed that four protomers initially form a tetramer, composed of a highly extended N-terminal region consisting of coiled-coil structures and C-terminal pentraxin domains, where two tetramers then immediately align and associate via an extensive network of salt bridges, allowing stabilisation of the octamer via the formation of disulphide bonds. However, a paper published around the same time provides an alternative perspective (Guo et al., 2025; DOI: 10.1016/j.ijbiomac.2024.139207). The authors propose, based on cryoEM analyses, that in addition to octamers, stable dimers, tetramers and hexamers of PTX3 can also assemble, where it is the dimers that provide the ‘building blocks’ for generation of the various oligomeric forms. In this commentary we suggest that the presence of dimers, tetramers and hexamers is likely an artefact of the construct used in recombinant expression, since the existence of these oligomers is not consistent with other studies on PTX3. We also provide a model to clarify how protomers become assembled into an octamer via sequential formation of a disulphide-linked tetramer, non-covalent association of two tetramers through aligned ionic interactions and the formation of disulphide bonds between the C-terminal pentraxin domains.
penttraxin -3 （PTX3）是一种分泌蛋白，在稳定富含透明质酸的细胞外基质中发挥作用，参与生殖生物学和炎症过程，以及在先天免疫和癌症中发挥额外功能。我们最近的结构研究(Shah et al., 2025；DOI:10.1016/j.matbio.2025.01.002)，涉及x射线晶体学，低温电子显微镜（cryoEM）和AlphaFold建模，提供了关于PTX3如何从八个相同的原聚体亚基组装成八聚体的线索。本文提出，四个原聚体最初形成一个四聚体，由一个高度延伸的n端区域组成，该区域由卷曲的线圈结构和c端戊烷素结构域组成，其中两个四聚体随后通过广泛的盐桥网络立即对齐并结合，从而通过形成二硫键来稳定八聚体。然而，大约在同一时间发表的一篇论文提供了另一种观点(Guo et al., 2025；DOI: 10.1016 / j.ijbiomac.2024.139207)。基于低温电镜分析，作者提出，除了八聚体外，PTX3的稳定二聚体、四聚体和六聚体也可以组装，其中二聚体为生成各种低聚体形式提供了“构建块”。在这篇评论中，我们认为二聚体、四聚体和六聚体的存在可能是重组表达中使用的结构的人工产物，因为这些低聚物的存在与其他关于PTX3的研究不一致。我们还提供了一个模型来阐明原聚体是如何通过二硫化物连接的四聚体的顺序形成、两个四聚体通过排列的离子相互作用的非共价结合以及在c端戊烷素结构域之间形成二硫化物键而组装成八聚体的。
{"title":"Oligomerisation of pentraxin-3: Insights from cryoEM","authors":"Antonio Inforzato , Anthony J. Day","doi":"10.1016/j.matbio.2025.04.001","DOIUrl":"10.1016/j.matbio.2025.04.001","url":null,"abstract":"<div><div>Pentraxin-3 (PTX3) is a secreted protein with roles in the stabilisation of hyaluronan-rich extracellular matrices involved in reproductive biology and inflammatory processes, as well as additional functions in innate immunity and cancer. Our recent structural studies (Shah <em>et al.</em>, 2025; DOI:10.1016/j.matbio.2025.01.002), involving X-ray crystallography, cryo-electron microscopy (cryoEM) and AlphaFold modelling, have provided clues as to how PTX3 becomes assembled into an octamer from eight identical protomer subunits. Here it was proposed that four protomers initially form a tetramer, composed of a highly extended N-terminal region consisting of coiled-coil structures and C-terminal pentraxin domains, where two tetramers then immediately align and associate via an extensive network of salt bridges, allowing stabilisation of the octamer via the formation of disulphide bonds. However, a paper published around the same time provides an alternative perspective (Guo <em>et al</em>., 2025; DOI: 10.1016/j.ijbiomac.2024.139207). The authors propose, based on cryoEM analyses, that in addition to octamers, stable dimers, tetramers and hexamers of PTX3 can also assemble, where it is the dimers that provide the ‘building blocks’ for generation of the various oligomeric forms. In this commentary we suggest that the presence of dimers, tetramers and hexamers is likely an artefact of the construct used in recombinant expression, since the existence of these oligomers is not consistent with other studies on PTX3. We also provide a model to clarify how protomers become assembled into an octamer via sequential formation of a disulphide-linked tetramer, non-covalent association of two tetramers through aligned ionic interactions and the formation of disulphide bonds between the C-terminal pentraxin domains.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"138 ","pages":"Pages 22-26"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789372","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}
Pub Date : 2025-06-01Epub Date: 2025-03-19DOI: 10.1016/j.matbio.2025.03.002
Anil A. Sohail , M. Kristian Koski , Lloyd W. Ruddock
Perlecan is an essential multi-domain, disulfide bond rich basement membrane protein. Mutations in perlecan cause Schwartz-Jampel syndrome and dyssegmental dysplasia. While there has been a large body of experimental work reported on perlecan, there is only minimal structural information available to date. There is no prior structural data for region 3 of perlecan in which some Schwartz-Jampel syndrome causing point mutations have been reported. Here, we produce constructs of the disulfide rich region 3 of perlecan along with five mutations previously reported to cause Schwatz-Jampel syndrome. Four of the mutations resulted in decreased yields and thermal stability compared to the wild-type protein. In contrast, the P1019L mutation was produced in good yields and showed higher thermal stability than the wild-type protein. The crystal structures for both the wild-type and P1019L mutation were solved. As expected, both showed laminin IV-like and laminin-type EGF-like domains, with the P1019L mutation resulting in only a minor conformational change in a loop region and no significant changes in regular secondary or tertiary structure.
{"title":"Structural insights on perlecan and Schwartz–Jampel syndrome","authors":"Anil A. Sohail , M. Kristian Koski , Lloyd W. Ruddock","doi":"10.1016/j.matbio.2025.03.002","DOIUrl":"10.1016/j.matbio.2025.03.002","url":null,"abstract":"<div><div>Perlecan is an essential multi-domain, disulfide bond rich basement membrane protein. Mutations in perlecan cause Schwartz-Jampel syndrome and dyssegmental dysplasia. While there has been a large body of experimental work reported on perlecan, there is only minimal structural information available to date. There is no prior structural data for region 3 of perlecan in which some Schwartz-Jampel syndrome causing point mutations have been reported. Here, we produce constructs of the disulfide rich region 3 of perlecan along with five mutations previously reported to cause Schwatz-Jampel syndrome. Four of the mutations resulted in decreased yields and thermal stability compared to the wild-type protein. In contrast, the P1019L mutation was produced in good yields and showed higher thermal stability than the wild-type protein. The crystal structures for both the wild-type and P1019L mutation were solved. As expected, both showed laminin IV-like and laminin-type EGF-like domains, with the P1019L mutation resulting in only a minor conformational change in a loop region and no significant changes in regular secondary or tertiary structure.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"138 ","pages":"Pages 1-7"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673661","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}
Pub Date : 2025-06-01Epub Date: 2025-03-28DOI: 10.1016/j.matbio.2025.03.003
Meysam Ganjibakhsh , Yanina Tkachenko , Russell H. Knutsen , Beth A. Kozel
Elastin is a connective tissue protein, produced from the ELN gene, that provides elasticity and recoil to tissues that stretch, such as the large arteries of the body, lung parenchyma, skin, ligaments and elastic cartilages. It is produced as a soluble monomer, tropoelastin, that when cross-linked in the extracellular space generates a polymer that is extraordinarily stable, with a predicted half-life of >70 years. Although data suggest ongoing elastin transcription, it is rare to see new elastin deposited outside of its tight developmental window. Consequently, elastin-related disease comes about primarily in one of three scenarios: (1) inadequate elastin deposition, (2) production of poor-quality elastic fibers, or (3) increased destruction of previously deposited elastin. By understanding the pathways controlling elastin production and maintenance, we can design new therapeutics to thwart those abnormal processes. In this review, we will summarize the diseases arising from genetic and environmental alteration of elastin (Williams syndrome, supravalvar aortic stenosis, autosomal dominant cutis laxa, and ELN-related vascular and connective tissue dysfunction) and then describe the mechanisms controlling elastin production and maintenance that might be manipulated to generate novel therapeutics aimed at these conditions. We will end by summarizing existing therapeutic strategies targeting these disease mechanisms before outlining future approaches that may better solve the challenges associated with elastin based regenerative medicine.
{"title":"Toward a rational therapeutic for elastin related disease: Key considerations for elastin based regenerative medicine strategies","authors":"Meysam Ganjibakhsh , Yanina Tkachenko , Russell H. Knutsen , Beth A. Kozel","doi":"10.1016/j.matbio.2025.03.003","DOIUrl":"10.1016/j.matbio.2025.03.003","url":null,"abstract":"<div><div>Elastin is a connective tissue protein, produced from the <em>ELN</em> gene, that provides elasticity and recoil to tissues that stretch, such as the large arteries of the body, lung parenchyma, skin, ligaments and elastic cartilages. It is produced as a soluble monomer, tropoelastin, that when cross-linked in the extracellular space generates a polymer that is extraordinarily stable, with a predicted half-life of >70 years. Although data suggest ongoing elastin transcription, it is rare to see new elastin deposited outside of its tight developmental window. Consequently, elastin-related disease comes about primarily in one of three scenarios: (1) inadequate elastin deposition, (2) production of poor-quality elastic fibers, or (3) increased destruction of previously deposited elastin. By understanding the pathways controlling elastin production and maintenance, we can design new therapeutics to thwart those abnormal processes. In this review, we will summarize the diseases arising from genetic and environmental alteration of elastin (Williams syndrome, supravalvar aortic stenosis, autosomal dominant cutis laxa, and ELN-related vascular and connective tissue dysfunction) and then describe the mechanisms controlling elastin production and maintenance that might be manipulated to generate novel therapeutics aimed at these conditions. We will end by summarizing existing therapeutic strategies targeting these disease mechanisms before outlining future approaches that may better solve the challenges associated with elastin based regenerative medicine.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"138 ","pages":"Pages 8-21"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755559","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}
Pub Date : 2025-06-01Epub Date: 2025-04-12DOI: 10.1016/j.matbio.2025.04.002
Md Al Azim, Julie S Di Martino
Collagen is the most abundant protein in mammals, significantly contributing to cancer progression. Cells express two primary well-conserved collagen receptors, integrins and discoidin domain receptors (DDRs), which bind collagen on distinct sites, suggesting that cancer cells must integrate both signals to decide their fate. The crosstalk between integrins and DDRs mediated by collagen binding produces dynamic, integrated signals that control tumor progression, therapeutic resistance, and cancer cell heterogeneity. This review will discuss the dynamic interplay among collagen, integrins, and DDRs in ECM remodeling during cancer progression and these receptors' crosstalk. In addition, we explored current and future directions for ECM receptor-targeted therapies, including nanotechnologies and precision medicine, to improve therapeutic outcomes by establishing a proper balance between integrins and DDRs in cancer.
{"title":"ECM, integrins, and DDRs: A nexus of cancer progression, therapy, and future directions","authors":"Md Al Azim, Julie S Di Martino","doi":"10.1016/j.matbio.2025.04.002","DOIUrl":"10.1016/j.matbio.2025.04.002","url":null,"abstract":"<div><div>Collagen is the most abundant protein in mammals, significantly contributing to cancer progression. Cells express two primary well-conserved collagen receptors, integrins and discoidin domain receptors (DDRs), which bind collagen on distinct sites, suggesting that cancer cells must integrate both signals to decide their fate. The crosstalk between integrins and DDRs mediated by collagen binding produces dynamic, integrated signals that control tumor progression, therapeutic resistance, and cancer cell heterogeneity. This review will discuss the dynamic interplay among collagen, integrins, and DDRs in ECM remodeling during cancer progression and these receptors' crosstalk. In addition, we explored current and future directions for ECM receptor-targeted therapies, including nanotechnologies and precision medicine, to improve therapeutic outcomes by establishing a proper balance between integrins and DDRs in cancer.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"138 ","pages":"Pages 27-43"},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824042","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}
Pub Date : 2025-05-01Epub Date: 2025-02-14DOI: 10.1016/j.matbio.2025.02.003
Hans Peter Bächinger , Sergei P. Boudko
The collagen triple helix is one of the structurally simplest protein motifs that still holds a lot of secrets. The Gly-X-Y repeat is a business card of collagens, where Gly is required for the tight packing of three helices into a superhelix and X and Y residues are important for stabilizing the triple helix and communicating with the world. On its way to a functional molecule, collagen sequences undergo unique post-translational modifications inside and outside of the cell. Moreover, folding and secretion of collagens require specific proteins and mechanisms. Cracking the collagen triple helix codes opens up opportunities for curing associated diseases and developing new biomaterials. Here, we summarized my journey through some mysteries of the collagen triple helix and point out key unaddressed questions and problems for other researchers to pursue.
{"title":"Mysteries of the collagen triple helix","authors":"Hans Peter Bächinger , Sergei P. Boudko","doi":"10.1016/j.matbio.2025.02.003","DOIUrl":"10.1016/j.matbio.2025.02.003","url":null,"abstract":"<div><div>The collagen triple helix is one of the structurally simplest protein motifs that still holds a lot of secrets. The Gly-X-Y repeat is a business card of collagens, where Gly is required for the tight packing of three helices into a superhelix and X and Y residues are important for stabilizing the triple helix and communicating with the world. On its way to a functional molecule, collagen sequences undergo unique post-translational modifications inside and outside of the cell. Moreover, folding and secretion of collagens require specific proteins and mechanisms. Cracking the collagen triple helix codes opens up opportunities for curing associated diseases and developing new biomaterials. Here, we summarized my journey through some mysteries of the collagen triple helix and point out key unaddressed questions and problems for other researchers to pursue.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"137 ","pages":"Pages 12-18"},"PeriodicalIF":4.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433939","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}
Pub Date : 2025-05-01Epub Date: 2025-03-02DOI: 10.1016/j.matbio.2025.03.001
Emily M. Martin , Joan Chang , Arantxa González , Federica Genovese
Collagen type I (COL1) is the most abundant protein in the human body and is a main component in the extracellular matrix. The COL1 structure vastly influences normal tissue homeostasis, and changes in the matrix drive progression in multiple diseases. Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity in many Western countries; alterations in the extracellular matrix turnover processes, including COL1, are known to influence the pathophysiological processes leading to CVD outcome. Peptides reflecting COL1 formation and degradation have been established and explored for over two decades in CVD. This review aims to combine and assess the evidence for using COL1-derived circulating peptides as biomarkers in CVD. Secondly, the review identifies existing pitfalls, and evaluates future opportunities for improving the technical characteristics and performance of the biomarkers for implementation in the clinical setting.
{"title":"Circulating collagen type I fragments as specific biomarkers of cardiovascular outcome risk: Where are the opportunities?","authors":"Emily M. Martin , Joan Chang , Arantxa González , Federica Genovese","doi":"10.1016/j.matbio.2025.03.001","DOIUrl":"10.1016/j.matbio.2025.03.001","url":null,"abstract":"<div><div>Collagen type I (COL1) is the most abundant protein in the human body and is a main component in the extracellular matrix. The COL1 structure vastly influences normal tissue homeostasis, and changes in the matrix drive progression in multiple diseases. Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity in many Western countries; alterations in the extracellular matrix turnover processes, including COL1, are known to influence the pathophysiological processes leading to CVD outcome. Peptides reflecting COL1 formation and degradation have been established and explored for over two decades in CVD. This review aims to combine and assess the evidence for using COL1-derived circulating peptides as biomarkers in CVD. Secondly, the review identifies existing pitfalls, and evaluates future opportunities for improving the technical characteristics and performance of the biomarkers for implementation in the clinical setting.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"137 ","pages":"Pages 19-32"},"PeriodicalIF":4.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558463","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}
Pub Date : 2025-05-01Epub Date: 2025-02-14DOI: 10.1016/j.matbio.2025.02.004
Ryan M. Friedman , Huy D. Truong , Matthew R. Aronson , Elizabeth A. Brown , Marco Angelozzi , Jeffrey F. Chen , Karen B. Zur , Véronique Lefebvre , Riccardo Gottardi
Vocal fold scarring, the most common cause of poor voice after airway injury, involves the transition of vocal fold fibroblasts to contractile myofibroblasts. Vocal fold myofibroblasts can be characterized by significant extracellular matrix (ECM) secretion and stress fiber formation. Biochemical signals, such as transforming growth factor (TGF)-β1, and biophysical cues, such as matrix stiffening, have been shown to induce the fibroblast-to-myofibroblast transition. To identify key intracellular pathways that may mediate myofibroblast activation, we performed bulk RNA sequencing of human vocal fold fibroblasts treated with or without TGF-β1 and found that genes downstream of myocardin related transcription factor A (MRTF-A) and serum response factor (SRF) were upregulated in TGFβ1-induced myofibroblasts. We then show that both TGF-β1 and ECM stiffening induce MRTF-A and SRF nuclear translocation during vocal fold myofibroblast activation. Inhibition of MRTF-A via CCG-257,081 reduced pro-fibrotic gene expression, the percentage of α-smooth muscle actin (α-SMA)-positive fibroblasts, and cell contractility in vitro. In a murine model of vocal fold scarring, MRTF-A inhibition reduced vocal fold scarring severity, evidenced by reduced epithelial thickening, decreased glycosaminoglycan content, and collagen deposition, and decreased expression of ACTA2. Our study suggests that the MRTF-A/SRF pathway regulates vocal fold myofibroblast activation, and that inhibition of MRTF-A has a protective effect against vocal fold scarring in mice.
{"title":"Inhibition of the MRTF-A/SRF signaling axis alleviates vocal fold scarring","authors":"Ryan M. Friedman , Huy D. Truong , Matthew R. Aronson , Elizabeth A. Brown , Marco Angelozzi , Jeffrey F. Chen , Karen B. Zur , Véronique Lefebvre , Riccardo Gottardi","doi":"10.1016/j.matbio.2025.02.004","DOIUrl":"10.1016/j.matbio.2025.02.004","url":null,"abstract":"<div><div>Vocal fold scarring, the most common cause of poor voice after airway injury, involves the transition of vocal fold fibroblasts to contractile myofibroblasts. Vocal fold myofibroblasts can be characterized by significant extracellular matrix (ECM) secretion and stress fiber formation. Biochemical signals, such as transforming growth factor (TGF)-β1, and biophysical cues, such as matrix stiffening, have been shown to induce the fibroblast-to-myofibroblast transition. To identify key intracellular pathways that may mediate myofibroblast activation, we performed bulk RNA sequencing of human vocal fold fibroblasts treated with or without TGF-β1 and found that genes downstream of myocardin related transcription factor A (MRTF-A) and serum response factor (SRF) were upregulated in TGFβ1-induced myofibroblasts. We then show that both TGF-β1 and ECM stiffening induce MRTF-A and SRF nuclear translocation during vocal fold myofibroblast activation. Inhibition of MRTF-A via CCG-257,081 reduced pro-fibrotic gene expression, the percentage of α-smooth muscle actin (α-SMA)-positive fibroblasts, and cell contractility <em>in vitro</em>. In a murine model of vocal fold scarring, MRTF-A inhibition reduced vocal fold scarring severity, evidenced by reduced epithelial thickening, decreased glycosaminoglycan content, and collagen deposition, and decreased expression of <em>ACTA2</em>. Our study suggests that the MRTF-A/SRF pathway regulates vocal fold myofibroblast activation, and that inhibition of MRTF-A has a protective effect against vocal fold scarring in mice.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"137 ","pages":"Pages 1-11"},"PeriodicalIF":4.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433802","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}
Pub Date : 2025-05-01Epub Date: 2025-03-01DOI: 10.1016/j.matbio.2025.02.005
Ava Nasrollahi, Yao Yao
The blood-brain barrier (BBB) is a dynamic structure that maintains brain homeostasis. BBB breakdown is a key pathological hallmark of almost all neurological diseases. Although the regulation of BBB integrity by different cells has been extensively studied, the function of its non-cellular component—the basal lamina in BBB regulation remains largely unknown. Laminin, a trimeric protein with multiple isoforms, is one of the most important constituents of the basal lamina. In the CNS, different cells synthesize distinct laminin isoforms, which differentially regulate BBB integrity in both physiological and pathological conditions. A thorough understanding of laminin expression and function in BBB integrity could lead to the identification of novel therapeutic targets and potentially result in effective treatments for neurological disorders involving BBB disruption. Here in this review, we first briefly introduce the BBB and basal lamina with a focus on laminin. Next, we elucidate laminin expression and its function in BBB maintenance/repair in a cell-specific manner. Potential functional compensation among laminin isoforms is also discussed. Last, current challenges in the field and future directions are summarized. Our goal is to provide a synthetic review to encourage novel ideas and stimulate new research in the field.
{"title":"Laminins and the blood-brain barrier","authors":"Ava Nasrollahi, Yao Yao","doi":"10.1016/j.matbio.2025.02.005","DOIUrl":"10.1016/j.matbio.2025.02.005","url":null,"abstract":"<div><div>The blood-brain barrier (BBB) is a dynamic structure that maintains brain homeostasis. BBB breakdown is a key pathological hallmark of almost all neurological diseases. Although the regulation of BBB integrity by different cells has been extensively studied, the function of its non-cellular component—the basal lamina in BBB regulation remains largely unknown. Laminin, a trimeric protein with multiple isoforms, is one of the most important constituents of the basal lamina. In the CNS, different cells synthesize distinct laminin isoforms, which differentially regulate BBB integrity in both physiological and pathological conditions. A thorough understanding of laminin expression and function in BBB integrity could lead to the identification of novel therapeutic targets and potentially result in effective treatments for neurological disorders involving BBB disruption. Here in this review, we first briefly introduce the BBB and basal lamina with a focus on laminin. Next, we elucidate laminin expression and its function in BBB maintenance/repair in a cell-specific manner. Potential functional compensation among laminin isoforms is also discussed. Last, current challenges in the field and future directions are summarized. Our goal is to provide a synthetic review to encourage novel ideas and stimulate new research in the field.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"137 ","pages":"Pages 33-41"},"PeriodicalIF":4.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544188","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}
Pub Date : 2025-04-01Epub Date: 2025-02-10DOI: 10.1016/j.matbio.2025.02.002
Jessica Oyie Sousa Onyeisi , Heba M. El-Shorafa , Burkhard Greve , Martin Götte
Syndecan-4 (SDC4), a heparan sulfate proteoglycan, is aberrantly expressed in breast cancer and plays a significant role in tumor progression by influencing cell proliferation and promoting invasive growth. This study aimed to characterize its role in the tumor microenvironment by analyzing the contribution of SDC4 to vasculogenic mimicry (VM) and angiogenesis in human breast cancer cells. We silenced SDC4 in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231, MDA-MB-468, and SUM-149 and analyzed its functions in vitro. SDC4 knockdown inhibited the VM of MDA-MB-231 cells as analyzed by fluorescence microscopy. Moreover, RT-qPCR revealed decreased expression of KLF4, EGR1, and HPSE, factors involved in VM, proangiogenic and pro-invasive processes in all TNBC cell lines. Western blotting revealed a partially cell-line-dependent regulation of these proteins by SDC4. At the functional level, SDC4 knockdown also impaired angiogenesis, decreasing the number of nodes and meshes in a 3D co-culture model comprising endothelial cells and TNBC cells. Using a Proteome Profile Human Angiogenesis Array, we observed that SDC4 knockdown decreased the secretion of VEGF and IGFBP-1, while it increased the secretion of IL-8, uPA, and amphiregulin in the conditioned media of the MDA-MB-231 and MDA-MB-468 co-cultures. Independent RT-qPCR analyses of gene expression were consistent with those of the angiogenesis array. Overall, these findings highlighted the crucial role of SDC4 in regulating both vasculogenic mimicry and angiogenesis in TNBC cells. The data indicate that SDC4 acts as a crucial regulatory molecule and represents a promising target for therapeutic strategies in breast cancer.
{"title":"Role of syndecan-4 in angiogenesis and vasculogenic mimicry in triple negative breast cancer cells","authors":"Jessica Oyie Sousa Onyeisi , Heba M. El-Shorafa , Burkhard Greve , Martin Götte","doi":"10.1016/j.matbio.2025.02.002","DOIUrl":"10.1016/j.matbio.2025.02.002","url":null,"abstract":"<div><div>Syndecan-4 (SDC4), a heparan sulfate proteoglycan, is aberrantly expressed in breast cancer and plays a significant role in tumor progression by influencing cell proliferation and promoting invasive growth. This study aimed to characterize its role in the tumor microenvironment by analyzing the contribution of SDC4 to vasculogenic mimicry (VM) and angiogenesis in human breast cancer cells. We silenced SDC4 in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231, MDA-MB-468, and SUM-149 and analyzed its functions in vitro. SDC4 knockdown inhibited the VM of MDA-MB-231 cells as analyzed by fluorescence microscopy. Moreover, RT-qPCR revealed decreased expression of KLF4, EGR1, and HPSE, factors involved in VM, proangiogenic and pro-invasive processes in all TNBC cell lines. Western blotting revealed a partially cell-line-dependent regulation of these proteins by SDC4. At the functional level, SDC4 knockdown also impaired angiogenesis, decreasing the number of nodes and meshes in a 3D co-culture model comprising endothelial cells and TNBC cells. Using a Proteome Profile Human Angiogenesis Array, we observed that SDC4 knockdown decreased the secretion of VEGF and IGFBP-1, while it increased the secretion of IL-8, uPA, and amphiregulin in the conditioned media of the MDA-MB-231 and MDA-MB-468 co-cultures. Independent RT-qPCR analyses of gene expression were consistent with those of the angiogenesis array. Overall, these findings highlighted the crucial role of SDC4 in regulating both vasculogenic mimicry and angiogenesis in TNBC cells. The data indicate that SDC4 acts as a crucial regulatory molecule and represents a promising target for therapeutic strategies in breast cancer.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 127-133"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411302","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}
Pub Date : 2025-04-01Epub Date: 2025-01-14DOI: 10.1016/j.matbio.2025.01.003
Feifei Li , Sandeep Kumar , Anastassia Pokutta-Paskaleva , Dong-won Kang , Chanwoo Kim , Julia Raykin , Victor Omojola , Carson Hoffmann , Fujie Zhao , Maiko Teichmann , Christian Park , Kyung In Baek , Gloriani Sanchez Marrero , Jing Ma , Hiromi Yanagisawa , Andrew Leask , Lucas Timmins , Xiangqin Cui , Roy Sutliff , Rudy L. Gleason Jr. , Luke P. Brewster
<div><div>Arterial endothelial cells (ECs) reside in a complex biomechanical environment. ECs sense and respond to wall shear stress. Low and oscillatory wall shear stress is characteristic of disturbed flow and commonly found at arterial bifurcations and around atherosclerotic plaques. Disturbed flow is pro-inflammatory to ECs. Arteries also stiffen with aging and/or the onset of vascular disease. ECs sense and respond to stiffening in a pro-fibrotic manner. Thus, flow and stiffening disturbances elicit EC responses that promote pathologic arterial remodeling. However, the pathways elicited by ECs under pathologic stiffening and disturbed flow are not well understood.</div><div>The objective of this work was to discover and test the modifiability of key pathways in ECs. To do this we used the partial carotid ligation model to impose disturbed flow onto the precociously stiffened fibulin-5 knockout (<em>Fbln5<sup>-/-</sup></em>) mouse carotid arteries. Biomechanical testing demonstrated that <em>Fbln5<sup>-/-</sup></em> arteries under disturbed flow approximate the stiffness ratio of diseased human arteries, and the ECs in these <em>Fbln5<sup>-/-</sup></em> arteries underwent rapid reprogramming via endothelial to mesenchymal transition (EndMT). Under atherogenic conditions, disturbed flow <em>Fbln5<sup>-/-</sup></em> arteries developed more vulnerable plaques than the wild type (WT) mouse arteries. Connective tissue growth factor/cellular communication network factor 2 (<em>Ctgf</em>/<em>Ccn2</em>) was upregulated in vivo in ECs with aging, with stiffening in the <em>Fbln5</em><sup>-/-</sup> arteries, and increased again by disturbed flow under stiffened conditions, supporting CTGF as a key biomarker for flow and stiffening. This was validated by immunohistochemistry, which demonstrated increased CTGF deposition in areas of disturbed flow in patient carotid endarterectomy and peripheral artery disease (PAD) specimens. Finally, to test the role of CTGF in regulating and combining these processes, we created an EC-specific <em>Ctgf</em> knockout (<em>Ctgf<sup>ecko</sup></em>). We identified that carotid arteries under disturbed flow and atherogenic conditions in male <em>Ctgf<sup>ecko</sup></em>, but not female, mice had decreased plaque area compared to WT control mice. We then tested the <em>Ctgf</em> expression in the carotid endothelium exposed to disturbed or stable flow in WT and <em>Fbln5<sup>-/-</sup></em> mice. Here we found that under disturbed flow male mice had greater <em>Ctgf</em> expression than female mice.</div><div>This work demonstrates that stiffened + disturbed flow conditions drive EC reprogramming, that CTGF is increased by these conditions, and that this increase is more prominent in male carotid arteries. Future exploration of sex-based differences in these fibrotic pathways are warranted to develop targeted therapeutics to limit pathologic arterial remodeling under pathologically stiffened + disturbed flow environments.</
{"title":"Endothelial cell (EC)-specific Ctgf/Ccn2 expression increases EC reprogramming and atherosclerosis","authors":"Feifei Li , Sandeep Kumar , Anastassia Pokutta-Paskaleva , Dong-won Kang , Chanwoo Kim , Julia Raykin , Victor Omojola , Carson Hoffmann , Fujie Zhao , Maiko Teichmann , Christian Park , Kyung In Baek , Gloriani Sanchez Marrero , Jing Ma , Hiromi Yanagisawa , Andrew Leask , Lucas Timmins , Xiangqin Cui , Roy Sutliff , Rudy L. Gleason Jr. , Luke P. Brewster","doi":"10.1016/j.matbio.2025.01.003","DOIUrl":"10.1016/j.matbio.2025.01.003","url":null,"abstract":"<div><div>Arterial endothelial cells (ECs) reside in a complex biomechanical environment. ECs sense and respond to wall shear stress. Low and oscillatory wall shear stress is characteristic of disturbed flow and commonly found at arterial bifurcations and around atherosclerotic plaques. Disturbed flow is pro-inflammatory to ECs. Arteries also stiffen with aging and/or the onset of vascular disease. ECs sense and respond to stiffening in a pro-fibrotic manner. Thus, flow and stiffening disturbances elicit EC responses that promote pathologic arterial remodeling. However, the pathways elicited by ECs under pathologic stiffening and disturbed flow are not well understood.</div><div>The objective of this work was to discover and test the modifiability of key pathways in ECs. To do this we used the partial carotid ligation model to impose disturbed flow onto the precociously stiffened fibulin-5 knockout (<em>Fbln5<sup>-/-</sup></em>) mouse carotid arteries. Biomechanical testing demonstrated that <em>Fbln5<sup>-/-</sup></em> arteries under disturbed flow approximate the stiffness ratio of diseased human arteries, and the ECs in these <em>Fbln5<sup>-/-</sup></em> arteries underwent rapid reprogramming via endothelial to mesenchymal transition (EndMT). Under atherogenic conditions, disturbed flow <em>Fbln5<sup>-/-</sup></em> arteries developed more vulnerable plaques than the wild type (WT) mouse arteries. Connective tissue growth factor/cellular communication network factor 2 (<em>Ctgf</em>/<em>Ccn2</em>) was upregulated in vivo in ECs with aging, with stiffening in the <em>Fbln5</em><sup>-/-</sup> arteries, and increased again by disturbed flow under stiffened conditions, supporting CTGF as a key biomarker for flow and stiffening. This was validated by immunohistochemistry, which demonstrated increased CTGF deposition in areas of disturbed flow in patient carotid endarterectomy and peripheral artery disease (PAD) specimens. Finally, to test the role of CTGF in regulating and combining these processes, we created an EC-specific <em>Ctgf</em> knockout (<em>Ctgf<sup>ecko</sup></em>). We identified that carotid arteries under disturbed flow and atherogenic conditions in male <em>Ctgf<sup>ecko</sup></em>, but not female, mice had decreased plaque area compared to WT control mice. We then tested the <em>Ctgf</em> expression in the carotid endothelium exposed to disturbed or stable flow in WT and <em>Fbln5<sup>-/-</sup></em> mice. Here we found that under disturbed flow male mice had greater <em>Ctgf</em> expression than female mice.</div><div>This work demonstrates that stiffened + disturbed flow conditions drive EC reprogramming, that CTGF is increased by these conditions, and that this increase is more prominent in male carotid arteries. Future exploration of sex-based differences in these fibrotic pathways are warranted to develop targeted therapeutics to limit pathologic arterial remodeling under pathologically stiffened + disturbed flow environments.</","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 102-110"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015188","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}
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