Pub Date : 2024-11-09DOI: 10.1016/j.matbio.2024.11.004
Brian C.H. Cheung , Xingyu Chen , Hannah J. Davis , Cassidy S. Nordmann , Joshua Toth , Louis Hodgson , Jeffrey E. Segall , Vivek B. Shenoy , Mingming Wu
Mechanical properties of the extracellular matrix (ECM) critically regulate a number of important cell functions including growth, differentiation and migration. Type I collagen and glycosaminoglycans (GAGs) are two primary components of ECMs that contribute to mammalian tissue mechanics, with the collagen fiber network sustaining tension, and GAGs withstanding compression. The architecture and stiffness of the collagen network are known to be important for cell-ECM mechanical interactions via cell surface adhesion receptor integrin. In contrast, studies of GAGs in modulating cell-ECM interactions are limited. Here, we present experimental studies on the roles of hyaluronic acid (HA) in single tumor cell traction force generation using a recently developed 3D cell traction force microscopy method. Our work reveals that CD44, a cell surface receptor to HA, is engaged in cell traction force generation in conjunction with β1-integrin. We find that HA significantly modifies the architecture and mechanics of the collagen fiber network, decreasing tumor cells’ propensity to remodel the collagen network, attenuating traction force generation, transmission distance, and tumor invasion. Our findings point to a novel role for CD44 in traction force generation, which can be a potential therapeutic target for diseases involving HA rich ECMs such as breast cancer and glioblastoma.
细胞外基质（ECM）的力学特性对许多重要的细胞功能（包括生长、分化和迁移）起着至关重要的调节作用。I 型胶原蛋白和糖胺聚糖（GAGs）是 ECM 的两种主要成分，它们对哺乳动物组织的力学性能起着重要作用。众所周知，胶原蛋白网络的结构和硬度通过整合素细胞表面粘附受体对细胞与 ECM 的机械相互作用非常重要。相比之下，对 GAGs 调节细胞-ECM 相互作用的研究却很有限。在此，我们采用最新开发的三维细胞牵引力显微镜方法，对透明质酸（HA）在单个肿瘤细胞牵引力产生中的作用进行了实验研究。我们的研究发现，细胞表面的 HA 受体 CD44 与 β1-integrin 共同参与了细胞牵引力的产生。我们发现 HA 能明显改变胶原纤维网络的结构和力学，降低肿瘤细胞重塑胶原网络的倾向，减少牵引力的产生、传输距离和肿瘤侵袭。我们的研究结果表明，CD44 在牵引力的产生过程中扮演着新的角色，可以成为乳腺癌和胶质母细胞瘤等涉及富含 HA 的 ECM 的疾病的潜在治疗靶点。
{"title":"Identification of CD44 as a key engager to hyaluronic acid-rich extracellular matrices for cell traction force generation and tumor invasion in 3D","authors":"Brian C.H. Cheung , Xingyu Chen , Hannah J. Davis , Cassidy S. Nordmann , Joshua Toth , Louis Hodgson , Jeffrey E. Segall , Vivek B. Shenoy , Mingming Wu","doi":"10.1016/j.matbio.2024.11.004","DOIUrl":"10.1016/j.matbio.2024.11.004","url":null,"abstract":"<div><div>Mechanical properties of the extracellular matrix (ECM) critically regulate a number of important cell functions including growth, differentiation and migration. Type I collagen and glycosaminoglycans (GAGs) are two primary components of ECMs that contribute to mammalian tissue mechanics, with the collagen fiber network sustaining tension, and GAGs withstanding compression. The architecture and stiffness of the collagen network are known to be important for cell-ECM mechanical interactions via cell surface adhesion receptor integrin. In contrast, studies of GAGs in modulating cell-ECM interactions are limited. Here, we present experimental studies on the roles of hyaluronic acid (HA) in single tumor cell traction force generation using a recently developed 3D cell traction force microscopy method. Our work reveals that CD44, a cell surface receptor to HA, is engaged in cell traction force generation in conjunction with β1-integrin. We find that HA significantly modifies the architecture and mechanics of the collagen fiber network, decreasing tumor cells’ propensity to remodel the collagen network, attenuating traction force generation, transmission distance, and tumor invasion. Our findings point to a novel role for CD44 in traction force generation, which can be a potential therapeutic target for diseases involving HA rich ECMs such as breast cancer and glioblastoma.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 1-11"},"PeriodicalIF":4.5,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631368","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 : 2024-11-03DOI: 10.1016/j.matbio.2024.10.007
Tomasz Wenta , Paulina Nastaly , Barbara Lipinska , Aki Manninen
The extracellular matrix (ECM) serves as a physical scaffold for tissues that is composed of structural proteins such as laminins, collagens, proteoglycans and fibronectin, forming a three dimensional network, and a wide variety of other matrix proteins with ECM-remodeling and signaling functions. The activity of ECM-associated signaling proteins is tightly regulated. Thus, the ECM serves as a reservoir for water and growth regulatory signals. The ECM architecture is dynamically modulated by multiple serine proteases that process both structural and signaling proteins to regulate physiological processes such as organogenesis and tissue homeostasis but they also contribute to pathological events, especially cancer progression. Here, we review the current literature regarding the role of ECM remodeling by serine proteases (KLKs, uPA, furin, HtrAs, granzymes, matriptase, hepsin) in tumorigenesis.
{"title":"Remodeling of the extracellular matrix by serine proteases as a prerequisite for cancer initiation and progression","authors":"Tomasz Wenta , Paulina Nastaly , Barbara Lipinska , Aki Manninen","doi":"10.1016/j.matbio.2024.10.007","DOIUrl":"10.1016/j.matbio.2024.10.007","url":null,"abstract":"<div><div>The extracellular matrix (ECM) serves as a physical scaffold for tissues that is composed of structural proteins such as laminins, collagens, proteoglycans and fibronectin, forming a three dimensional network, and a wide variety of other matrix proteins with ECM-remodeling and signaling functions. The activity of ECM-associated signaling proteins is tightly regulated. Thus, the ECM serves as a reservoir for water and growth regulatory signals. The ECM architecture is dynamically modulated by multiple serine proteases that process both structural and signaling proteins to regulate physiological processes such as organogenesis and tissue homeostasis but they also contribute to pathological events, especially cancer progression. Here, we review the current literature regarding the role of ECM remodeling by serine proteases (KLKs, uPA, furin, HtrAs, granzymes, matriptase, hepsin) in tumorigenesis.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 197-219"},"PeriodicalIF":4.5,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584786","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 : 2024-11-02DOI: 10.1016/j.matbio.2024.11.002
Whitney M. Longmate
Integrins are cellular transmembrane receptors that physically connect the cytoskeleton with the extracellular matrix. As such, they are positioned to mediate cellular responses to microenvironmental cues. Importantly, integrins also regulate their own microenvironment through secreted factors, also known as the integrin-mediated secretome. Epidermal integrins, or integrins expressed by keratinocytes of the skin epidermis, regulate the cutaneous microenvironment through the contribution of matrix components, via proteolytic matrix remodeling, or by mediating factors like cytokines and growth factors that can promote support for nearby but distinct cells of the stroma, such as immune cells, endothelial cells, and fibroblasts. This role for integrins is enhanced during both pathological and repair tissue remodeling processes, such as tumor growth and progression and wound healing. This review will discuss examples of how the epithelial integrin-mediated secretome can regulate the tissue microenvironment. Although different epithelial integrins in various contexts will be explored, emphasis will be given to epidermal integrins that regulate the secretome during wound healing and cutaneous tumor progression. Epidermal integrin α3β1 is of particular focus as well, since this integrin has been revealed as a key regulator of the keratinocyte secretome.
{"title":"The epidermal integrin-mediated secretome regulates the skin microenvironment during tumorigenesis and repair","authors":"Whitney M. Longmate","doi":"10.1016/j.matbio.2024.11.002","DOIUrl":"10.1016/j.matbio.2024.11.002","url":null,"abstract":"<div><div>Integrins are cellular transmembrane receptors that physically connect the cytoskeleton with the extracellular matrix. As such, they are positioned to mediate cellular responses to microenvironmental cues. Importantly, integrins also regulate their own microenvironment through secreted factors, also known as the integrin-mediated secretome. Epidermal integrins, or integrins expressed by keratinocytes of the skin epidermis, regulate the cutaneous microenvironment through the contribution of matrix components, via proteolytic matrix remodeling, or by mediating factors like cytokines and growth factors that can promote support for nearby but distinct cells of the stroma, such as immune cells, endothelial cells, and fibroblasts. This role for integrins is enhanced during both pathological and repair tissue remodeling processes, such as tumor growth and progression and wound healing. This review will discuss examples of how the epithelial integrin-mediated secretome can regulate the tissue microenvironment. Although different epithelial integrins in various contexts will be explored, emphasis will be given to epidermal integrins that regulate the secretome during wound healing and cutaneous tumor progression. Epidermal integrin α3β1 is of particular focus as well, since this integrin has been revealed as a key regulator of the keratinocyte secretome.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 175-183"},"PeriodicalIF":4.5,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567833","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 : 2024-11-02DOI: 10.1016/j.matbio.2024.11.001
Jadwiga Jabłońska , Grzegorz Wiera , Jerzy W. Mozrzymas
The brain's extracellular matrix (ECM) is crucial for neural circuit functionality, synaptic plasticity, and learning. While the role of the ECM in excitatory synapses has been extensively studied, its influence on inhibitory synapses, particularly on GABAergic long-term plasticity, remains poorly understood. This study aims to elucidate the effects of ECM components on inhibitory synaptic transmission and plasticity in the hippocampal CA1 region. We focus on the roles of chondroitin sulfate proteoglycans (CSPGs) and hyaluronic acid in modulating inhibitory postsynaptic currents (IPSCs) at two distinct inhibitory synapses formed by somatostatin (SST)-positive and parvalbumin (PV)-positive interneurons onto pyramidal cells (PCs). Using optogenetic stimulation in brain slices, we observed that acute degradation of ECM constituents by hyaluronidase or chondroitinase-ABC did not affect basal inhibitory synaptic transmission. However, short-term plasticity, particularly burst-induced depression, was enhanced at PV→PC synapses following enzymatic treatments. Long-term plasticity experiments demonstrated that CSPGs are essential for NMDA-induced iLTP at SST→PC synapses, whereas the digestion of hyaluronic acid by hyaluronidase impaired iLTP at PV→PC synapses. This indicates a synapse-specific role of CSPGs and hyaluronic acid in regulating GABAergic plasticity. Additionally, we report the presence of cryptic GABAergic plasticity at PV→PC synapses induced by prolonged NMDA application, which became evident after CSPG digestion and was absent under control conditions. Our results underscore the differential impact of ECM degradation on inhibitory synaptic plasticity, highlighting the synapse-specific interplay between ECM components and specific GABAergic synapses. This offers new perspectives in studies on learning and critical period timing.
{"title":"Extracellular matrix integrity regulates GABAergic plasticity in the hippocampus","authors":"Jadwiga Jabłońska , Grzegorz Wiera , Jerzy W. Mozrzymas","doi":"10.1016/j.matbio.2024.11.001","DOIUrl":"10.1016/j.matbio.2024.11.001","url":null,"abstract":"<div><div>The brain's extracellular matrix (ECM) is crucial for neural circuit functionality, synaptic plasticity, and learning. While the role of the ECM in excitatory synapses has been extensively studied, its influence on inhibitory synapses, particularly on GABAergic long-term plasticity, remains poorly understood. This study aims to elucidate the effects of ECM components on inhibitory synaptic transmission and plasticity in the hippocampal CA1 region. We focus on the roles of chondroitin sulfate proteoglycans (CSPGs) and hyaluronic acid in modulating inhibitory postsynaptic currents (IPSCs) at two distinct inhibitory synapses formed by somatostatin (SST)-positive and parvalbumin (PV)-positive interneurons onto pyramidal cells (PCs). Using optogenetic stimulation in brain slices, we observed that acute degradation of ECM constituents by hyaluronidase or chondroitinase-ABC did not affect basal inhibitory synaptic transmission. However, short-term plasticity, particularly burst-induced depression, was enhanced at PV→PC synapses following enzymatic treatments. Long-term plasticity experiments demonstrated that CSPGs are essential for NMDA-induced iLTP at SST→PC synapses, whereas the digestion of hyaluronic acid by hyaluronidase impaired iLTP at PV→PC synapses. This indicates a synapse-specific role of CSPGs and hyaluronic acid in regulating GABAergic plasticity. Additionally, we report the presence of cryptic GABAergic plasticity at PV→PC synapses induced by prolonged NMDA application, which became evident after CSPG digestion and was absent under control conditions. Our results underscore the differential impact of ECM degradation on inhibitory synaptic plasticity, highlighting the synapse-specific interplay between ECM components and specific GABAergic synapses. This offers new perspectives in studies on learning and critical period timing.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 184-196"},"PeriodicalIF":4.5,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570349","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 : 2024-10-18DOI: 10.1016/j.matbio.2024.10.005
Hayato L. Mizuno , James D. Kang , Shuichi Mizuno
Spinal movement in both upright and recumbent positions generates changes in physicochemical stresses including hydrostatic pressure (HP), deviatoric stress, and confinement within the intradiscal compartment. The nucleus pulposus (NP) of the intervertebral disc is composed of highly negatively charged extracellular matrix (ECM), which increases osmotic pressure (OP) and generates tissue swelling. In pursuing regenerative therapies for intervertebral disc degeneration, the effects of HP on the cellular responses of NP cells and the ECM environment remain incompletely understood. We hypothesized that anabolic turnover of ECM in NP tissue is maintained under HP and confinement. We first clarified the effects of the relationships among HP, OP, and confinement on swelling NP explants isolated from bovine caudal intervertebral discs over 12 h. We found that the application of confinement and constant HP significantly inhibits the free swelling of NP (p < 0.01) and helps retain the sulfated glycosaminoglycan. Since confinement and HP inhibited swelling, we incubated confined NPs under HP in high-osmolality medium mimicking ECM-associated OP for 7 days and demonstrated the effects of HP on metabolic turnover of ECM molecules in NP cells. The aggrecan core protein gene was significantly upregulated under confinement and constant HP compared to confinement and no HP (p < 0.01). We also found that confinement and constant HP helped to significantly retain smaller cell area (p < 0.01) and significantly prevent the severing of actin filaments compared to no confinement and HP (p < 0.01). Thus, we suggest that NP's metabolic turnover and cellular responses are regulated by the configuration of intracellular actin and fibrillar ECMs under HP.
脊柱在直立和仰卧姿势下的运动会产生物理化学应力的变化，包括静水压力（HP）、偏差应力和椎间盘内的束缚。椎间盘的髓核（NP）由带高负电荷的细胞外基质（ECM）组成，这会增加渗透压（OP）并导致组织肿胀。在寻求椎间盘变性再生疗法的过程中，HP 对 NP 细胞的细胞反应和 ECM 环境的影响仍未得到充分了解。我们假设，在 HP 和封闭条件下，NP 组织中的 ECM 可维持合成代谢。我们首先阐明了 HP、OP 和封闭之间的关系对 12 小时内从牛尾椎间盘分离出的膨胀 NP 外植体的影响。我们发现，封闭和恒定的 HP 能明显抑制 NP 的自由膨胀（p < 0.01），并有助于保留硫酸化的糖胺聚糖。由于封闭和 HP 可抑制肿胀，我们在模拟 ECM 相关 OP 的高渗透压培养基中培养了 HP 下的封闭 NP 7 天，并证明了 HP 对 NP 细胞中 ECM 分子代谢的影响。与封闭和无 HP 相比，在封闭和恒定 HP 条件下，凝集素核心蛋白基因明显上调（p < 0.01）。我们还发现，与无封闭和恒定 HP 相比，封闭和恒定 HP 有助于明显保留较小的细胞面积（p < 0.01），并能明显防止肌动蛋白丝的切断（p < 0.01）。因此，我们认为 NP 的新陈代谢和细胞反应受 HP 下细胞内肌动蛋白和纤维 ECM 配置的调节。
{"title":"Effects of hydrostatic pressure, osmotic pressure, and confinement on extracellular matrix associated responses in the nucleus pulposus cells ex vivo","authors":"Hayato L. Mizuno , James D. Kang , Shuichi Mizuno","doi":"10.1016/j.matbio.2024.10.005","DOIUrl":"10.1016/j.matbio.2024.10.005","url":null,"abstract":"<div><div>Spinal movement in both upright and recumbent positions generates changes in physicochemical stresses including hydrostatic pressure (HP), deviatoric stress, and confinement within the intradiscal compartment. The nucleus pulposus (NP) of the intervertebral disc is composed of highly negatively charged extracellular matrix (ECM), which increases osmotic pressure (OP) and generates tissue swelling. In pursuing regenerative therapies for intervertebral disc degeneration, the effects of HP on the cellular responses of NP cells and the ECM environment remain incompletely understood. We hypothesized that anabolic turnover of ECM in NP tissue is maintained under HP and confinement. We first clarified the effects of the relationships among HP, OP, and confinement on swelling NP explants isolated from bovine caudal intervertebral discs over 12 h. We found that the application of confinement and constant HP significantly inhibits the free swelling of NP (<em>p</em> < 0.01) and helps retain the sulfated glycosaminoglycan. Since confinement and HP inhibited swelling, we incubated confined NPs under HP in high-osmolality medium mimicking ECM-associated OP for 7 days and demonstrated the effects of HP on metabolic turnover of ECM molecules in NP cells. The aggrecan core protein gene was significantly upregulated under confinement and constant HP compared to confinement and no HP (<em>p</em> < 0.01). We also found that confinement and constant HP helped to significantly retain smaller cell area (<em>p</em> < 0.01) and significantly prevent the severing of actin filaments compared to no confinement and HP (<em>p</em> < 0.01). Thus, we suggest that NP's metabolic turnover and cellular responses are regulated by the configuration of intracellular actin and fibrillar ECMs under HP.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 162-174"},"PeriodicalIF":4.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479184","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 : 2024-10-13DOI: 10.1016/j.matbio.2024.10.006
Moses Musiime , Pugazendhi Murugan Erusappan , Edna Cukierman , Joan Chang , Anders Molven , Uwe Hansen , Cédric Zeltz , Donald Gullberg
Solid epithelial cancers with significant desmoplasia are characterized by an excessive deposition of collagen-based matrix, which often supports tumor progression. However, the mechanism of how collagen receptors mediate collagen fibrillogenesis still remains mostly unclear.
We show that the collagen-binding integrin α11β1 can co-localize with tensin-1 and deposited collagen I in human pancreatic ductal adenocarcinoma (PDAC) stroma. In addition to the canonical fibrillar adhesion integrin α5β1 expressed by human PDAC cancer-associated fibroblasts (CAFs), tensin-1-positive fibrillar adhesions contained α11β1 but lacked α1β1 and α2β1. CAFs lacking α5β1 expression displayed mechanoregulated and tensin-1 dependent α11β1 fibrillar adhesions, suggesting independent roles of the two integrins with regards to fibrillar adhesions-based de novo fibrillogenesis. Further, we demonstrate that cell surface-associated collagen I assembly necessitated α11β1, but not α5β1 expression.
In summary, α11β1 integrin is a novel component of fibrillar adhesions, which is strategically positioned to mediate de novo collagen fibrillogenesis at the cell surface under pro-fibrotic conditions.
有明显脱钙化的实体上皮癌的特点是胶原基质的过度沉积，这通常会支持肿瘤的进展。然而，胶原受体如何介导胶原纤维生成的机制仍大多不清楚。我们的研究表明，胶原结合整合素α11β1能与tensin-1共定位，并在人胰腺导管腺癌（PDAC）基质中沉积胶原蛋白I。除了人PDAC癌相关成纤维细胞（CAFs）表达的典型纤维粘附整合素α5β1外，tensin-1阳性纤维粘附还包含α11β1，但缺乏α1β1和α2β1。缺乏α5β1表达的CAF显示出机械调节的、依赖于tensin-1的α11β1纤维粘附，这表明这两种整合素在基于纤维粘附的新生纤维形成中发挥着独立的作用。此外，我们还证明细胞表面相关的胶原 I 组装需要α11β1，而不是α5β1的表达。总之，α11β1整合素是纤维粘连的一种新成分，在促纤维化条件下，它具有介导细胞表面新生胶原纤维形成的战略地位。
{"title":"Fibroblast integrin α11β1 is a collagen assembly receptor in mechanoregulated fibrillar adhesions","authors":"Moses Musiime , Pugazendhi Murugan Erusappan , Edna Cukierman , Joan Chang , Anders Molven , Uwe Hansen , Cédric Zeltz , Donald Gullberg","doi":"10.1016/j.matbio.2024.10.006","DOIUrl":"10.1016/j.matbio.2024.10.006","url":null,"abstract":"<div><div>Solid epithelial cancers with significant desmoplasia are characterized by an excessive deposition of collagen-based matrix, which often supports tumor progression. However, the mechanism of how collagen receptors mediate collagen fibrillogenesis still remains mostly unclear.</div><div>We show that the collagen-binding integrin α11β1 can co-localize with tensin-1 and deposited collagen I in human pancreatic ductal adenocarcinoma (PDAC) stroma. In addition to the canonical fibrillar adhesion integrin α5β1 expressed by human PDAC cancer-associated fibroblasts (CAFs), tensin-1-positive fibrillar adhesions contained α11β1 but lacked α1β1 and α2β1. CAFs lacking α5β1 expression displayed mechanoregulated and tensin-1 dependent α11β1 fibrillar adhesions, suggesting independent roles of the two integrins with regards to fibrillar adhesions-based de novo fibrillogenesis. Further, we demonstrate that cell surface-associated collagen I assembly necessitated α11β1, but not α5β1 expression.</div><div>In summary, α11β1 integrin is a novel component of fibrillar adhesions, which is strategically positioned to mediate de novo collagen fibrillogenesis at the cell surface under pro-fibrotic conditions.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 144-161"},"PeriodicalIF":4.5,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479185","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 : 2024-10-11DOI: 10.1016/j.matbio.2024.10.001
Yunkyoung Ryu , Je Hyun Seo , Hak Su Kim , Youn Joo Nam , Kyung Bo Noh , Sun-Hee Oh , Jin Sun Hwang , Young Joo Shin
Corneal endothelial cells (CECs) are essential for maintaining corneal transparency and hydration through their barrier and pump functions. The COL8A2 gene encodes a component of the extracellular matrix of the cornea, which is crucial for the normal functioning of these cells. Mutations in COL8A2 are linked to corneal dystrophies, emphasizing the gene's importance in corneal health. The purpose of this research is to explore the effects of COL8A2 activation within CECs, to understand its contribution to cellular behavior and health. COL8A2 CRISPR/dCas9 activation system (aCOL8A2) was used to activate the COL8A2. In rats, wound healing and mitochondrial function were assessed after COL8A2 activation. As a result, aCOL8A2 promoted wound healing of rat corneal endothelium by increasing mitochondrial membrane potential. In cultured human CECs, proteomic analysis was performed to screen and identify the differential protein profiles between control and aCOL8A2 cells. Western blot was used to validate the differential proteins from both cells. Mitochondrial function and intracellular distribution were assessed by measuring ATP production and mitochondrial membrane potential. In cultured human CECs, aCOL8A2 increased COL8A2 and phospho-YAP levels. Transendothelial electrical resistance (TEER) was increased and actin cytoskeleton was attenuated by aCOL8A2. Gene ontology analysis revealed that the proteins were mainly involved in the regulation of folate biosynthesis, ECM-receptor interaction, cell differentiation, NADP activity and cytoskeleton. ATP production was increased, mitochondrial membrane potential was polarized and mitochondrial distribution was widespread in the aCOL8A2 group. In conclusion, aCOL8A2 induces a regulatory cascade affecting mitochondrial positioning and efficiency, mediated by alterations in the cytoskeletal architecture and the YAP signaling pathway. This sequence of events serves to bolster the functional capacities of corneal endothelial cells, including their pump and barrier functions, essential for corneal health and transparency.
{"title":"COL8A2 activation enhances function of corneal endothelial cells through HIPPO signaling/mitochondria pathway","authors":"Yunkyoung Ryu , Je Hyun Seo , Hak Su Kim , Youn Joo Nam , Kyung Bo Noh , Sun-Hee Oh , Jin Sun Hwang , Young Joo Shin","doi":"10.1016/j.matbio.2024.10.001","DOIUrl":"10.1016/j.matbio.2024.10.001","url":null,"abstract":"<div><div>Corneal endothelial cells (CECs) are essential for maintaining corneal transparency and hydration through their barrier and pump functions. The <em>COL8A2</em> gene encodes a component of the extracellular matrix of the cornea, which is crucial for the normal functioning of these cells. Mutations in <em>COL8A2</em> are linked to corneal dystrophies, emphasizing the gene's importance in corneal health. The purpose of this research is to explore the effects of <em>COL8A2</em> activation within CECs, to understand its contribution to cellular behavior and health. <em>COL8A2</em> CRISPR/dCas9 activation system (aCOL8A2) was used to activate the <em>COL8A2</em>. In rats, wound healing and mitochondrial function were assessed after <em>COL8A2</em> activation. As a result, aCOL8A2 promoted wound healing of rat corneal endothelium by increasing mitochondrial membrane potential. In cultured human CECs, proteomic analysis was performed to screen and identify the differential protein profiles between control and aCOL8A2 cells. Western blot was used to validate the differential proteins from both cells. Mitochondrial function and intracellular distribution were assessed by measuring ATP production and mitochondrial membrane potential. In cultured human CECs, aCOL8A2 increased COL8A2 and phospho-YAP levels. Transendothelial electrical resistance (TEER) was increased and actin cytoskeleton was attenuated by aCOL8A2. Gene ontology analysis revealed that the proteins were mainly involved in the regulation of folate biosynthesis, ECM-receptor interaction, cell differentiation, NADP activity and cytoskeleton. ATP production was increased, mitochondrial membrane potential was polarized and mitochondrial distribution was widespread in the aCOL8A2 group. In conclusion, aCOL8A2 induces a regulatory cascade affecting mitochondrial positioning and efficiency, mediated by alterations in the cytoskeletal architecture and the YAP signaling pathway. This sequence of events serves to bolster the functional capacities of corneal endothelial cells, including their pump and barrier functions, essential for corneal health and transparency.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 119-131"},"PeriodicalIF":4.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442008","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 : 2024-10-10DOI: 10.1016/j.matbio.2024.10.004
Cheng Miao , Liu Liu , Yubin Cao , Zhishen Jiang , Zhangfan Ding , Yafei Chen , Honglin Li , Zhongkai Ma , Pingchuan Ma , Gaowei Zhang , Longjiang Li , Chunjie Li
Cancer-associated myofibroblasts (mCAFs) represent a significant component of the tumor microenvironment due to their contributions to extracellular matrix (ECM) remodeling. The pro-tumor mechanisms of extracellular vesicles (EVs) by regulating mCAFs and related collagens remain poorly understood in oral squamous cell carcinoma (OSCC). In this study, through analysis of single-cell sequencing data and immunofluorescence staining, we confirmed the increased presence of mCAFs and enrichment of specific collagen types in OSCC tissues. Furthermore, we demonstrated that OSCC-derived EVs promote the transformation of fibroblasts into mCAFs, leading to tumor invasion. Proteomic analysis identified the presence of TGF-β1 in EVs and revealed its role in inducing mCAFs via the TGF-β1/SMAD signaling pathway. Experiments in vivo confirmed that EVs, particularly those carrying TGF-β1, trigger COL18high COL5high matrix deposition, thereby forming the pro-tumor ECM in OSCC. In summary, our investigation unveils the significant involvement of OSCC-derived EVs in orchestrating the differentiation of fibroblasts into mCAFs and modulating specific collagen types within the ECM. Therefore, this study provides a theoretical basis for targeting the EV-mediated TGF-β1 signaling pathway as a potential therapeutic strategy for OSCC.
{"title":"OSCC-derived EVs educate fibroblasts and remodel collagen landscape","authors":"Cheng Miao , Liu Liu , Yubin Cao , Zhishen Jiang , Zhangfan Ding , Yafei Chen , Honglin Li , Zhongkai Ma , Pingchuan Ma , Gaowei Zhang , Longjiang Li , Chunjie Li","doi":"10.1016/j.matbio.2024.10.004","DOIUrl":"10.1016/j.matbio.2024.10.004","url":null,"abstract":"<div><div>Cancer-associated myofibroblasts (mCAFs) represent a significant component of the tumor microenvironment due to their contributions to extracellular matrix (ECM) remodeling. The pro-tumor mechanisms of extracellular vesicles (EVs) by regulating mCAFs and related collagens remain poorly understood in oral squamous cell carcinoma (OSCC). In this study, through analysis of single-cell sequencing data and immunofluorescence staining, we confirmed the increased presence of mCAFs and enrichment of specific collagen types in OSCC tissues. Furthermore, we demonstrated that OSCC-derived EVs promote the transformation of fibroblasts into mCAFs, leading to tumor invasion. Proteomic analysis identified the presence of TGF-β1 in EVs and revealed its role in inducing mCAFs via the TGF-β1/SMAD signaling pathway. Experiments <em>in vivo</em> confirmed that EVs, particularly those carrying TGF-β1, trigger COL18<sup>high</sup> COL5<sup>high</sup> matrix deposition, thereby forming the pro-tumor ECM in OSCC. In summary, our investigation unveils the significant involvement of OSCC-derived EVs in orchestrating the differentiation of fibroblasts into mCAFs and modulating specific collagen types within the ECM. Therefore, this study provides a theoretical basis for targeting the EV-mediated TGF-β1 signaling pathway as a potential therapeutic strategy for OSCC.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 132-143"},"PeriodicalIF":4.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407110","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 : 2024-10-05DOI: 10.1016/j.matbio.2024.10.003
Ming Liu , Hanshu Zhang , Yuanyuan Li , Delan Huang , Huanyan Zuo , Jingwen Yang , Zhi Chen
Cranial sutures function as growth centers for calvarial bones. Abnormal suture closure will cause permanent cranium deformities. MMP9 is a member of the gelatinases that degrades components of the extracellular matrix. MMP9 has been reported to regulate bone development and remodeling. However, the function of MMP9 in cranial suture development is still unknown. Here, we identified that the expression of Mmp9 was specifically elevated during fusion of posterior frontal (PF) suture compared with other patent sutures in mice. Interestingly, inhibition of MMP9 ex vivo or knockout of Mmp9 in mice (Mmp9-/-) disturbed the fusion of PF suture. Histological analysis showed that knockout of Mmp9 resulted in wider distance between osteogenic fronts, suppressed cell condensation and endocranial bone formation in PF suture. Proliferation, chondrogenesis and osteogenesis of suture cells were decreased in Mmp9-/- mice, leading to the PF suture defects. Moreover, transcriptome analysis of PF suture revealed upregulated ribosome biogenesis and downregulated IGF signaling associated with abnormal closure of PF suture in Mmp9-/- mice. Inhibition of the ribosome biogenesis partially rescued PF suture defects caused by Mmp9 knockout. Altogether, these results indicate that MMP9 is critical for the fusion of cranial sutures, thus suggesting MMP9 as a potential therapeutic target for cranial suture diseases.
{"title":"Loss of MMP9 disturbs cranial suture fusion via suppressing cell proliferation, chondrogenesis and osteogenesis in mice","authors":"Ming Liu , Hanshu Zhang , Yuanyuan Li , Delan Huang , Huanyan Zuo , Jingwen Yang , Zhi Chen","doi":"10.1016/j.matbio.2024.10.003","DOIUrl":"10.1016/j.matbio.2024.10.003","url":null,"abstract":"<div><div>Cranial sutures function as growth centers for calvarial bones. Abnormal suture closure will cause permanent cranium deformities. MMP9 is a member of the gelatinases that degrades components of the extracellular matrix. MMP9 has been reported to regulate bone development and remodeling. However, the function of MMP9 in cranial suture development is still unknown. Here, we identified that the expression of <em>Mmp9</em> was specifically elevated during fusion of posterior frontal (PF) suture compared with other patent sutures in mice. Interestingly, inhibition of MMP9 <em>ex vivo</em> or knockout of <em>Mmp9</em> in mice (<em>Mmp9<sup>-/-</sup></em>) disturbed the fusion of PF suture. Histological analysis showed that knockout of <em>Mmp9</em> resulted in wider distance between osteogenic fronts, suppressed cell condensation and endocranial bone formation in PF suture. Proliferation, chondrogenesis and osteogenesis of suture cells were decreased in <em>Mmp9<sup>-/-</sup></em> mice, leading to the PF suture defects. Moreover, transcriptome analysis of PF suture revealed upregulated ribosome biogenesis and downregulated IGF signaling associated with abnormal closure of PF suture in <em>Mmp9<sup>-/-</sup></em> mice. Inhibition of the ribosome biogenesis partially rescued PF suture defects caused by <em>Mmp9</em> knockout. Altogether, these results indicate that MMP9 is critical for the fusion of cranial sutures, thus suggesting MMP9 as a potential therapeutic target for cranial suture diseases.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 93-106"},"PeriodicalIF":4.5,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394779","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 : 2024-10-04DOI: 10.1016/j.matbio.2024.10.002
Anna K. Whitehead , Zhangjie Wang , Rebecca-Joe Boustany , Romain R. Vivès , Eric Lazartigues , Jian Liu , Robert W. Siggins , Xinping Yue
The heparan sulfate (HS) 6-O-endosulfatases or the Sulfs (Sulf1 and Sulf2) are the only known enzymes that can modify HS sulfation status extracellularly and have been shown to regulate diverse biological processes. The role of the Sulfs in bone marrow (BM) hematopoiesis is not known. In this study, we generated a novel mouse line with myeloid-specific deletion of the Sulfs by crossing Sulf1/2 double floxed mice with the LysM-cre line. The LysM-Sulf knockout (KO) male mice exhibited age-dependent expansion of hematopoietic stem cells and the granulocyte-monocyte lineages in the BM, whereas common lymphoid progenitors and B lymphocyte populations were significantly reduced. Although megakaryocytic and erythroid progenitors were not reduced in the BM, the LysM-Sulf KO males suffered age-dependent reduction of red blood cells (RBCs) and platelets in the peripheral blood, suggesting that the production of RBCs and platelets was arrested at later stages. In addition, LysM-Sulf KO males displayed progressive splenomegaly with extramedullary hematopoiesis. Compared to males, LysM-Sulf KO females exhibited a much-reduced phenotype, and ovariectomy had little effect. Mechanistically, reduced TGF-β/Smad2 but enhanced p53/p21 signaling were observed in male but not female LysM-Sulf KO mice. Finally, HS disaccharide analysis via LC-MS/MS revealed increased HS 6-O-sulfation in the BM from both male and female LysM-Sulf KO mice, however, the distribution of 6-O-sulfated motifs were different between the sexes with compensatory increase in Sulf1 expression observed only in LysM-Sulf KO females. In conclusion, our study reveals that myeloid deficiency of the Sulfs leads to multilineage abnormalities in BM hematopoiesis in an age- and sex-dependent manner.
硫酸肝素（HS）6-O-内切硫酸酯酶或硫酸内切酶（Sulf1 和 Sulf2）是目前已知的唯一能在细胞外改变硫酸肝素硫酸化状态的酶，已被证明能调节多种生物过程。Sulfs在骨髓（BM）造血中的作用尚不清楚。在这项研究中，我们通过将 Sulf1/2 双基因缺失小鼠与 LysM-cre 株系杂交，产生了一种髓系特异性缺失 Sulfs 的新型小鼠株系。LysM-Sulf基因敲除（KO）雄性小鼠的造血干细胞和粒细胞-单核细胞系表现出年龄依赖性扩增，而普通淋巴祖细胞和B淋巴细胞群则显著减少。虽然巨核细胞和红细胞祖细胞在骨髓中没有减少，但 LysM-Sulf KO 雄鼠外周血中红细胞和血小板的减少与年龄有关，这表明红细胞和血小板的生成在晚期阶段停止了。此外，LysM-Sulf KO 雄鼠表现出进行性脾肿大和髓外造血。与雄性相比，LysM-Sulf KO 的雌性表现出的表型大大降低，卵巢切除几乎没有影响。从机理上讲，在雄性而非雌性LysM-Sulf KO小鼠中观察到TGF-β/Smad2减少，但p53/p21信号增强。最后，通过LC-MS/MS进行的HS双糖分析表明，雄性和雌性LysM-Sulf KO小鼠骨髓中的HS 6-O-硫酸化均有所增加，但6-O-硫酸化基团的分布在雌雄小鼠中有所不同，仅在LysM-Sulf KO雌性小鼠中观察到Sulf1表达的代偿性增加。总之，我们的研究揭示了髓鞘Sulfs的缺乏会以年龄和性别依赖的方式导致骨髓造血的多系异常。
{"title":"Myeloid deficiency of heparan sulfate 6-O-endosulfatases impairs bone marrow hematopoiesis","authors":"Anna K. Whitehead , Zhangjie Wang , Rebecca-Joe Boustany , Romain R. Vivès , Eric Lazartigues , Jian Liu , Robert W. Siggins , Xinping Yue","doi":"10.1016/j.matbio.2024.10.002","DOIUrl":"10.1016/j.matbio.2024.10.002","url":null,"abstract":"<div><div>The heparan sulfate (HS) 6-<em>O</em>-endosulfatases or the Sulfs (Sulf1 and Sulf2) are the only known enzymes that can modify HS sulfation status extracellularly and have been shown to regulate diverse biological processes. The role of the Sulfs in bone marrow (BM) hematopoiesis is not known. In this study, we generated a novel mouse line with myeloid-specific deletion of the Sulfs by crossing Sulf1/2 double floxed mice with the <em>LysM-cre</em> line. The <em>LysM-Sulf</em> knockout (KO) male mice exhibited age-dependent expansion of hematopoietic stem cells and the granulocyte-monocyte lineages in the BM, whereas common lymphoid progenitors and B lymphocyte populations were significantly reduced. Although megakaryocytic and erythroid progenitors were not reduced in the BM, the <em>LysM-Sulf</em> KO males suffered age-dependent reduction of red blood cells (RBCs) and platelets in the peripheral blood, suggesting that the production of RBCs and platelets was arrested at later stages. In addition, <em>LysM-Sulf</em> KO males displayed progressive splenomegaly with extramedullary hematopoiesis. Compared to males, <em>LysM-Sulf</em> KO females exhibited a much-reduced phenotype, and ovariectomy had little effect. Mechanistically, reduced TGF-β/Smad2 but enhanced p53/p21 signaling were observed in male but not female <em>LysM-Sulf</em> KO mice. Finally, HS disaccharide analysis via LC-MS/MS revealed increased HS 6-<em>O</em>-sulfation in the BM from both male and female <em>LysM-Sulf</em> KO mice, however, the distribution of 6-<em>O</em>-sulfated motifs were different between the sexes with compensatory increase in Sulf1 expression observed only in <em>LysM-Sulf</em> KO females. In conclusion, our study reveals that myeloid deficiency of the Sulfs leads to multilineage abnormalities in BM hematopoiesis in an age- and sex-dependent manner.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"134 ","pages":"Pages 107-118"},"PeriodicalIF":4.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378505","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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