首页 > 最新文献

Matrix Biology最新文献

英文 中文
Spatial localization of collagen hydroxylated proline site variation as an ancestral trait in the breast cancer microenvironment 乳腺癌微环境中胶原羟基化脯氨酸位点变异作为祖先性状的空间定位
IF 4.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-23 DOI: 10.1016/j.matbio.2025.01.006
Harrison Taylor , Laura Spruill , Heather Jensen-Smith , Denys Rujchanarong , Taylor Hulahan , Ashlyn Ivey , Alex Siougiannis , Jennifer R. Bethard , Lauren E. Ball , George E. Sandusky , M.A. Hollingsworth , Jeremy L. Barth , Anand S. Mehta , Richard R. Drake , Jeffrey R. Marks , Harikrishna Nakshatri , Marvella Ford , Peggi M. Angel
Collagen stroma interactions within the extracellular microenvironment of breast tissue play a significant role in breast cancer, including risk, progression, and outcomes. Hydroxylation of proline (HYP) is a common post-translational modification directly linked to breast cancer survival and progression. Changes in HYP status lead to alterations in epithelial cell signaling, extracellular matrix remodeling, and immune cell recruitment. In the present study, we test the hypothesis that the breast cancer microenvironment presents unique PTMs of collagen, which form bioactive domains at these sites that are associated with spatial histopathological characteristics and influence breast epithelial cell signaling. Mass spectrometry imaging proteomics targeting collagens were paired with comprehensive proteomic methods to identify novel breast cancer-related collagen domains based on spatial localization and regulation in 260 breast tissue samples. As ancestry plays a significant role in breast cancer outcomes, these methods were performed on ancestry diverse breast cancer tissues. Lumpectomies from the Cancer Genome Atlas (TCGA; n=10) reported increased levels of prolyl 4-hydroxylase subunit alpha-3 (P4HA3) accompanied by spatial regulation of fibrillar collagen protein sequences. A concise set of triple negative breast cancer lumpectomies (n=10) showed spatial regulation of specific domain sites from collagen alpha-1(I) chain. Tissue microarrays identified proteomic alterations around post-translationally modified collagen sites in healthy breast (n=81) and patient matched normal adjacent (NAT; n=76) and invasive ductal carcinoma (n=83). A collagen alpha-1(I) chain domain encompassing amino acids 506–514 with site-specific proline hydroxylation reported significant alteration between patient matched normal adjacent tissue and invasive breast cancer. Functional testing of domain 506–514 on breast cancer epithelial cells showed proliferation, chemotaxis and cell signaling response dependent on site localization of proline hydroxylation within domain 506–514 variants. These findings support site localized collagen HYP forms novel bioactive domains that are spatially distributed within the breast cancer microenvironment and may play a role in ancestral traits of breast cancer.
乳腺组织细胞外微环境中胶原基质的相互作用对乳腺癌的风险、进展和预后起着重要作用。脯氨酸羟化（HYP）是一种常见的翻译后修饰，与乳腺癌的生存和发展直接相关。HYP 状态的变化会导致上皮细胞信号转导、细胞外基质重塑和免疫细胞招募发生改变。在本研究中，我们检验了乳腺癌微环境中胶原蛋白独特的 PTMs 假设，这些 PTMs 在这些部位形成生物活性域，与空间组织病理学特征相关，并影响乳腺上皮细胞信号转导。针对胶原蛋白的质谱成像蛋白质组学与综合蛋白质组学方法相配合，根据260个乳腺组织样本中的空间定位和调控，鉴定出新型的乳腺癌相关胶原蛋白结构域。由于血统在乳腺癌结果中起着重要作用，这些方法是在不同血统的乳腺癌组织中进行的。来自癌症基因组图谱（TCGA；n=10）的切除报告显示，脯氨酰4-羟化酶亚基α-3（P4HA3）水平升高，同时伴有纤维胶原蛋白序列的空间调控。一组简明的三阴性乳腺癌肿块切除术（n=10）显示了胶原蛋白α-1（I）链特定结构域位点的空间调控。组织微阵列确定了健康乳房（81 人）、与患者匹配的正常邻近乳房（NAT；76 人）和浸润性导管癌（83 人）中翻译后修饰的胶原蛋白位点周围的蛋白质组变化。据报告，在患者匹配的正常邻近组织和浸润性乳腺癌之间，包含氨基酸 506-514 的胶原蛋白α-1（I）链结构域发生了显著的脯氨酸羟基化位点改变。结构域 506-514 对乳腺癌上皮细胞的功能测试显示，乳腺癌细胞的增殖、趋化和细胞信号反应取决于结构域 506-514 变体中脯氨酸羟基化的位点定位。这些研究结果表明，局部胶原 HYP 形成了新的生物活性结构域，这些结构域在乳腺癌微环境中呈空间分布，并可能在乳腺癌的祖先特征中发挥作用。
{"title":"Spatial localization of collagen hydroxylated proline site variation as an ancestral trait in the breast cancer microenvironment","authors":"Harrison Taylor ,&nbsp;Laura Spruill ,&nbsp;Heather Jensen-Smith ,&nbsp;Denys Rujchanarong ,&nbsp;Taylor Hulahan ,&nbsp;Ashlyn Ivey ,&nbsp;Alex Siougiannis ,&nbsp;Jennifer R. Bethard ,&nbsp;Lauren E. Ball ,&nbsp;George E. Sandusky ,&nbsp;M.A. Hollingsworth ,&nbsp;Jeremy L. Barth ,&nbsp;Anand S. Mehta ,&nbsp;Richard R. Drake ,&nbsp;Jeffrey R. Marks ,&nbsp;Harikrishna Nakshatri ,&nbsp;Marvella Ford ,&nbsp;Peggi M. Angel","doi":"10.1016/j.matbio.2025.01.006","DOIUrl":"10.1016/j.matbio.2025.01.006","url":null,"abstract":"<div><div>Collagen stroma interactions within the extracellular microenvironment of breast tissue play a significant role in breast cancer, including risk, progression, and outcomes. Hydroxylation of proline (HYP) is a common post-translational modification directly linked to breast cancer survival and progression. Changes in HYP status lead to alterations in epithelial cell signaling, extracellular matrix remodeling, and immune cell recruitment. In the present study, we test the hypothesis that the breast cancer microenvironment presents unique PTMs of collagen, which form bioactive domains at these sites that are associated with spatial histopathological characteristics and influence breast epithelial cell signaling. Mass spectrometry imaging proteomics targeting collagens were paired with comprehensive proteomic methods to identify novel breast cancer-related collagen domains based on spatial localization and regulation in 260 breast tissue samples. As ancestry plays a significant role in breast cancer outcomes, these methods were performed on ancestry diverse breast cancer tissues. Lumpectomies from the Cancer Genome Atlas (TCGA; n=10) reported increased levels of prolyl 4-hydroxylase subunit alpha-3 (P4HA3) accompanied by spatial regulation of fibrillar collagen protein sequences. A concise set of triple negative breast cancer lumpectomies (n=10) showed spatial regulation of specific domain sites from collagen alpha-1(I) chain. Tissue microarrays identified proteomic alterations around post-translationally modified collagen sites in healthy breast (n=81) and patient matched normal adjacent (NAT; n=76) and invasive ductal carcinoma (n=83). A collagen alpha-1(I) chain domain encompassing amino acids 506–514 with site-specific proline hydroxylation reported significant alteration between patient matched normal adjacent tissue and invasive breast cancer. Functional testing of domain 506–514 on breast cancer epithelial cells showed proliferation, chemotaxis and cell signaling response dependent on site localization of proline hydroxylation within domain 506–514 variants. These findings support site localized collagen HYP forms novel bioactive domains that are spatially distributed within the breast cancer microenvironment and may play a role in ancestral traits of breast cancer.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 71-86"},"PeriodicalIF":4.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042706","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}
引用次数: 0
CD45+/ Col I+ Fibrocytes: Major source of collagen in the fibrotic lung, but not in passaged fibroblast cultures CD45+/ Col I+纤维细胞：纤维化肺中胶原蛋白的主要来源，但在传代成纤维细胞培养中不是。
IF 4.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-17 DOI: 10.1016/j.matbio.2025.01.005
Charles F. Reese , Monika Gooz , Zoltan Hajdu , Stanley Hoffman
The role of cells of the hematopoietic lineage in fibrosis is controversial. Here we evaluate the contribution of Col I+/CD45+ cells (fibrocytes) to lung fibrosis. Systemic bleomycin treatment was used to induce fibrosis in a bone marrow transplant and two transgenic mouse models. Lung cells from these mice were analyzed by flow cytometry, both immediately upon release from the tissue or following growth on tissue-culture plastic. Fibrotic and control human lung tissue were also used. Fibroblasts and fibrocytes derived from a transgenic mouse model were compared in terms of their morphology, growth, and adhesion to fibronectin. Single cell RNAseq was performed with the analysis focusing on CD45-/Col I+ “fibroblasts” and CD45+/Col I+ “fibrocytes” in control and fibrotic mouse lung tissue. Finally, we inhibited fibrosis in mice using a novel, water-soluble version of caveolin scaffolding domain (CSD) called WCSD.
In both mouse and human lung tissue, we observed by flow cytometry a large increase in fibrocyte number and Col I expression associated with fibrosis. In contrast, fibroblast number was not significantly increased. A large increase (>50-fold) in fibrocyte number associated with fibrosis was also observed by single cell RNAseq. In this case, fibroblasts increased 5-fold. Single cell RNAseq also revealed that myofibroblast markers in fibrotic tissue are associated with a cluster containing a similar number of fibrocytes and fibroblasts, not with a resident fibroblast cluster. Some investigators claim that fibrocytes are not present among primary fibroblasts. However, we found that fibrocytes were the predominant cell type present in these cultures prior to passage. Fewer fibrocytes were present after one passage, and almost none after two passages. Our experiments suggest that fibrocytes are crowded out of cultures during passage because fibroblasts have a larger footprint than fibrocytes, even though fibrocytes bind more efficiently to fibronectin. Finally, we observed by flow cytometry that in mice treated with bleomycin and WCSD compared to bleomycin alone, there was a large decrease in the number of fibrocytes present but not in the number of fibroblasts. In summary, fibrocytes are a major collagen-producing cell type that is increased in number in association with fibrosis as well as a major source of myofibroblasts. The common observation that collagen-producing spindle-shaped cells associated with fibrosis are CD45- may be an artifact of passage in cell culture.
造血系细胞在纤维化中的作用是有争议的。在这里，我们评估Col I+/CD45+细胞（纤维细胞）在肺纤维化中的作用。在骨髓移植和两个转基因小鼠模型中，全身性博来霉素治疗可诱导纤维化。通过流式细胞术分析这些小鼠的肺细胞，无论是在组织释放后立即还是在组织培养塑料上生长后。纤维化和对照人肺组织也被使用。我们比较了从转基因小鼠模型中提取的成纤维细胞和成纤维细胞的形态、生长和对纤维连接蛋白的粘附。单细胞RNAseq分析集中在对照和纤维化小鼠肺组织中的CD45-/Col I+“成纤维细胞”和CD45+/Col I+“纤维细胞”。最后，我们使用一种新的、水溶性的小窝蛋白支架结构域（CSD），即WCSD，抑制了小鼠的纤维化。在小鼠和人肺组织中，我们通过流式细胞术观察到与纤维化相关的纤维细胞数量和Col I表达的大量增加。相反，成纤维细胞数量没有显著增加。单细胞RNAseq也观察到与纤维化相关的纤维细胞数量大幅增加（50倍）。在这种情况下，成纤维细胞增加了5倍。单细胞RNAseq还显示，纤维化组织中的肌成纤维细胞标记与含有相似数量的纤维细胞和成纤维细胞的簇相关，而与驻留的成纤维细胞簇无关。一些研究者声称在原代成纤维细胞中不存在纤维细胞。然而，我们发现在传代之前，纤维细胞是这些培养中主要的细胞类型。一次传代后纤维细胞减少，两次传代后几乎没有。我们的实验表明，在传代过程中，纤维细胞被挤出培养物，因为成纤维细胞比纤维细胞有更大的足迹，尽管纤维细胞与纤维连接蛋白结合更有效。最后，我们通过流式细胞术观察到，与单独使用博来霉素相比，博来霉素和WCSD治疗小鼠的纤维细胞数量大幅减少，但成纤维细胞数量没有减少。综上所述，纤维细胞是一种主要的胶原生成细胞类型，其数量的增加与纤维化有关，也是肌成纤维细胞的主要来源。通常观察到与纤维化相关的胶原产生梭形细胞是CD45-，这可能是细胞培养传代的伪产物。
{"title":"CD45+/ Col I+ Fibrocytes: Major source of collagen in the fibrotic lung, but not in passaged fibroblast cultures","authors":"Charles F. Reese ,&nbsp;Monika Gooz ,&nbsp;Zoltan Hajdu ,&nbsp;Stanley Hoffman","doi":"10.1016/j.matbio.2025.01.005","DOIUrl":"10.1016/j.matbio.2025.01.005","url":null,"abstract":"<div><div>The role of cells of the hematopoietic lineage in fibrosis is controversial. Here we evaluate the contribution of Col I+/CD45+ cells (fibrocytes) to lung fibrosis. Systemic bleomycin treatment was used to induce fibrosis in a bone marrow transplant and two transgenic mouse models. Lung cells from these mice were analyzed by flow cytometry, both immediately upon release from the tissue or following growth on tissue-culture plastic. Fibrotic and control human lung tissue were also used. Fibroblasts and fibrocytes derived from a transgenic mouse model were compared in terms of their morphology, growth, and adhesion to fibronectin. Single cell RNAseq was performed with the analysis focusing on CD45-/Col <em>I</em>+ “fibroblasts” and CD45+/Col <em>I</em>+ “fibrocytes” in control and fibrotic mouse lung tissue. Finally, we inhibited fibrosis in mice using a novel, water-soluble version of caveolin scaffolding domain (CSD) called WCSD.</div><div>In both mouse and human lung tissue, we observed by flow cytometry a large increase in fibrocyte number and Col I expression associated with fibrosis. In contrast, fibroblast number was not significantly increased. A large increase (&gt;50-fold) in fibrocyte number associated with fibrosis was also observed by single cell RNAseq. In this case, fibroblasts increased 5-fold. Single cell RNAseq also revealed that myofibroblast markers in fibrotic tissue are associated with a cluster containing a similar number of fibrocytes and fibroblasts, not with a resident fibroblast cluster. Some investigators claim that fibrocytes are not present among primary fibroblasts. However, we found that fibrocytes were the predominant cell type present in these cultures prior to passage. Fewer fibrocytes were present after one passage, and almost none after two passages. Our experiments suggest that fibrocytes are crowded out of cultures during passage because fibroblasts have a larger footprint than fibrocytes, even though fibrocytes bind more efficiently to fibronectin. Finally, we observed by flow cytometry that in mice treated with bleomycin and WCSD compared to bleomycin alone, there was a large decrease in the number of fibrocytes present but not in the number of fibroblasts. In summary, fibrocytes are a major collagen-producing cell type that is increased in number in association with fibrosis as well as a major source of myofibroblasts. The common observation that collagen-producing spindle-shaped cells associated with fibrosis are CD45- may be an artifact of passage in cell culture.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 87-101"},"PeriodicalIF":4.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015184","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}
引用次数: 0
Decoding the MMP14 integrin link: Key player in the secretome landscape 解码MMP14整合素链接：分泌组景观的关键参与者。
IF 4.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-17 DOI: 10.1016/j.matbio.2025.01.004
Stephan Niland, Johannes A. Eble
Rapid progress has been made in the exciting field of secretome research in health and disease. The tumor secretome, which is a significant proportion of the tumor proteome, is secreted into the extracellular space to promote intercellular communication and thus tumor progression. Among the many molecules of the secretome, integrins and matrix metalloproteinase 14 (MMP14) stand out as the interplay of adhesion and proteolysis drives invasion. Integrins serve as mechanosensors that mediate the contact of cells with the scaffold of the extracellular matrix and are significantly involved in the precise positioning and activity control of the membrane-bound collagenase MMP14. As a secretome proteinase, MMP14 influences and modifies the secretome itself. While integrins and MT-MMPs are membrane bound, but can be released and are therefore border crossers between the cell surface and the secretome, the extracellular matrix is not constitutively cell-bound, but its binding to integrins and other cell receptors is a stringently regulated process. To understand the mutual interactions in detail, we first summarize the structure and function of MMP14 and how it is regulated at the enzymatic and cellular level. In particular, the mutual interactions between integrins and MMP14 include the proteolytic cleavage of integrins themselves by MMP14. We then review the biochemical, cell biological and physiological effects of MMP14 on the composition and associated functions in the tumor secretome when either bound to the cell membrane, or located on extracellular microvesicles, or as a proteolytically shed non-membrane-bound ectodomain. Novel methods of proteomics, including the analysis of extravesicular vesicles, and new methods for the quantification of MMP14 will provide new research and diagnostic tools. The proteolytic modification of the tumor secretome, especially by MMP14, may bring an additional aspect to tumor secretome studies and will have an impact on the diagnosis and most likely also on the therapy of cancer patients.
分泌组在健康和疾病领域的研究进展迅速。肿瘤分泌组是肿瘤蛋白质组的重要组成部分，分泌到细胞外空间，促进细胞间的通讯，从而促进肿瘤的进展。在分泌组的许多分子中，整合素和基质金属蛋白酶14 （MMP14）作为粘附和蛋白水解的相互作用驱动入侵而脱颖而出。整合素作为机械传感器，介导细胞与细胞外基质支架的接触，并在膜结合胶原酶MMP14的精确定位和活性控制中发挥重要作用。作为一种分泌组蛋白酶，MMP14影响和修饰分泌组本身。虽然整合素和MT-MMPs是膜结合的，但可以释放，因此是细胞表面和分泌组之间的边界交叉点，但细胞外基质不是构成细胞结合的，但其与整合素和其他细胞受体的结合是一个严格调节的过程。为了更详细地了解它们之间的相互作用，我们首先总结了MMP14的结构和功能，以及它是如何在酶和细胞水平上被调节的。特别是，整合素和MMP14之间的相互作用包括MMP14对整合素本身的蛋白水解裂解。然后，我们回顾了MMP14对肿瘤分泌组的组成和相关功能的生化、细胞生物学和生理学影响，无论是结合到细胞膜上，还是位于细胞外微泡上，或者作为蛋白水解脱落的非膜结合外域。包括囊外囊泡分析在内的蛋白质组学新方法和MMP14的定量新方法将提供新的研究和诊断工具。肿瘤分泌组的蛋白水解修饰，尤其是MMP14的修饰，可能会给肿瘤分泌组的研究带来额外的方面，并将对癌症患者的诊断产生影响，很可能也会对癌症患者的治疗产生影响。
{"title":"Decoding the MMP14 integrin link: Key player in the secretome landscape","authors":"Stephan Niland,&nbsp;Johannes A. Eble","doi":"10.1016/j.matbio.2025.01.004","DOIUrl":"10.1016/j.matbio.2025.01.004","url":null,"abstract":"<div><div>Rapid progress has been made in the exciting field of secretome research in health and disease. The tumor secretome, which is a significant proportion of the tumor proteome, is secreted into the extracellular space to promote intercellular communication and thus tumor progression. Among the many molecules of the secretome, integrins and matrix metalloproteinase 14 (MMP14) stand out as the interplay of adhesion and proteolysis drives invasion. Integrins serve as mechanosensors that mediate the contact of cells with the scaffold of the extracellular matrix and are significantly involved in the precise positioning and activity control of the membrane-bound collagenase MMP14. As a secretome proteinase, MMP14 influences and modifies the secretome itself. While integrins and MT-MMPs are membrane bound, but can be released and are therefore border crossers between the cell surface and the secretome, the extracellular matrix is not constitutively cell-bound, but its binding to integrins and other cell receptors is a stringently regulated process. To understand the mutual interactions in detail, we first summarize the structure and function of MMP14 and how it is regulated at the enzymatic and cellular level. In particular, the mutual interactions between integrins and MMP14 include the proteolytic cleavage of integrins themselves by MMP14. We then review the biochemical, cell biological and physiological effects of MMP14 on the composition and associated functions in the tumor secretome when either bound to the cell membrane, or located on extracellular microvesicles, or as a proteolytically shed non-membrane-bound ectodomain. Novel methods of proteomics, including the analysis of extravesicular vesicles, and new methods for the quantification of MMP14 will provide new research and diagnostic tools. The proteolytic modification of the tumor secretome, especially by MMP14, may bring an additional aspect to tumor secretome studies and will have an impact on the diagnosis and most likely also on the therapy of cancer patients.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 36-51"},"PeriodicalIF":4.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015186","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}
引用次数: 0
Endothelial cell (EC)-specific Ctgf/Ccn2 expression increases EC reprogramming and atherosclerosis 内皮细胞（EC）特异性CTGF/CCN2表达增加EC重编程和动脉粥样硬化
IF 4.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-14 DOI: 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
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.
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 (Fbln5-/-) mouse carotid arteries. Biomechanical testing demonstrated that Fbln5-/- arteries under disturbed flow approximate the stiffness ratio of diseased human arteries, and the ECs in these Fbln5-/- arteries underwent rapid reprogramming via endothelial to mesenchymal transition (EndMT). Under atherogenic conditions, disturbed flow Fbln5-/- arteries developed more vulnerable plaques than the wild type (WT) mouse arteries. Connective tissue growth factor/cellular communication network factor 2 (Ctgf/Ccn2) was upregulated in vivo in ECs with aging, with stiffening in the Fbln5-/- 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 Ctgf knockout (Ctgfecko). We identified that carotid arteries under disturbed flow and atherogenic conditions in male Ctgfecko, but not female, mice had decreased plaque area compared to WT control mice. We then tested the Ctgf expression in the carotid endothelium exposed to disturbed or stable flow in WT and Fbln5-/- mice. Here we found that under disturbed flow male mice had greater Ctgf expression than female mice.
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.
动脉内皮细胞（ECs）生活在一个复杂的生物力学环境中。ECs感知并响应壁面剪应力。低且振荡的壁剪应力是血流紊乱的特征，常见于动脉分叉处和动脉粥样硬化斑块周围。血流紊乱对内皮细胞有促炎作用。动脉也会随着年龄的增长和/或血管疾病的发生而变硬。内皮细胞以促纤维化的方式感知和响应硬化。因此，血流和硬化紊乱引起EC反应，促进病理性动脉重塑。然而，在病理性硬化和血流紊乱的情况下，内皮细胞所引发的途径尚不清楚。这项工作的目的是发现和测试ECs关键通路的可修饰性。为此，我们使用部分颈动脉结扎模型，对纤维蛋白-5敲除（Fbln5-/-）小鼠颈动脉施加干扰血流。生物力学测试表明，Fbln5-/-动脉在血流干扰下的刚度比接近人类病变动脉，这些Fbln5-/-动脉中的内皮细胞通过内皮细胞到间充质细胞的转化（EndMT）进行了快速重编程。在动脉粥样硬化条件下，血流紊乱的Fbln5-/-动脉比野生型（WT）小鼠动脉更容易形成斑块。结缔组织生长因子/细胞通信网络因子2 （Ctgf/Ccn2）在ec体内随着年龄的增长而上调，Fbln5-/-动脉硬化，在硬化条件下因血流紊乱而再次升高，支持Ctgf作为血流和硬化的关键生物标志物。免疫组织化学证实了这一点，在患者颈动脉内膜切除术和外周动脉病变（PAD）标本中，CTGF沉积在血流紊乱区域增加。最后，为了测试CTGF在调节和结合这些过程中的作用，我们创建了ec特异性CTGF敲除（Ctgfecko）。我们发现，在血流紊乱和动脉粥样硬化条件下，雄性Ctgfecko小鼠的颈动脉斑块面积比WT对照组小鼠减少，而雌性小鼠则没有。然后，我们测试了Ctgf在WT和Fbln5-/-小鼠颈动脉内皮中受干扰或稳定血流影响的表达。我们发现，在水流干扰下，雄性小鼠的Ctgf表达高于雌性小鼠。这项工作表明，硬化 + 紊乱的血流条件驱动EC重编程，CTGF在这些条件下增加，并且这种增加在男性颈动脉中更为突出。未来探索这些纤维化途径的性别差异是有必要的，以开发有针对性的治疗方法，以限制病理性硬化 + 紊乱血流环境下的病理性动脉重塑。
{"title":"Endothelial cell (EC)-specific Ctgf/Ccn2 expression increases EC reprogramming and atherosclerosis","authors":"Feifei Li ,&nbsp;Sandeep Kumar ,&nbsp;Anastassia Pokutta-Paskaleva ,&nbsp;Dong-won Kang ,&nbsp;Chanwoo Kim ,&nbsp;Julia Raykin ,&nbsp;Victor Omojola ,&nbsp;Carson Hoffmann ,&nbsp;Fujie Zhao ,&nbsp;Maiko Teichmann ,&nbsp;Christian Park ,&nbsp;Kyung In Baek ,&nbsp;Gloriani Sanchez Marrero ,&nbsp;Jing Ma ,&nbsp;Hiromi Yanagisawa ,&nbsp;Andrew Leask ,&nbsp;Lucas Timmins ,&nbsp;Xiangqin Cui ,&nbsp;Roy Sutliff ,&nbsp;Rudy L. Gleason Jr. ,&nbsp;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":"2025-01-14","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}
引用次数: 0
The structural organisation of pentraxin-3 and its interactions with heavy chains of inter-α-inhibitor regulate crosslinking of the hyaluronan matrix 戊烷素-3的结构组织及其与α-抑制剂重链的相互作用调节透明质酸基质的交联。
IF 4.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-13 DOI: 10.1016/j.matbio.2025.01.002
Anokhi Shah , Xiaoli Zhang , Matthew Snee , Michael P. Lockhart-Cairns , Colin W. Levy , Thomas A. Jowitt , Holly L. Birchenough , Louisa Dean , Richard Collins , Rebecca J. Dodd , Abigail R.E. Roberts , Jan J. Enghild , Alberto Mantovani , Juan Fontana , Clair Baldock , Antonio Inforzato , Ralf P. Richter , Anthony J. Day
Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large polysaccharide hyaluronan (HA) to which heavy chains (HCs) of the inter-α-inhibitor (IαI) family of proteoglycans are covalently attached, playing a key role in the (non-covalent) crosslinking of HC•HA complexes. These interactions stabilise the cumulus matrix, essential for ovulation and fertilisation in mammals, and are also implicated in the formation of pathogenic matrices in the context of viral lung infections. To better understand the physiological and pathological roles of PTX3 we have analysed how its quaternary structure underpins HA crosslinking via its interactions with HCs. A combination of X-ray crystallography, cryo-electron microscopy (cryo-EM) and AlphaFold predictive modelling revealed that the C-terminal pentraxin domains of the PTX3 octamer are arranged in a central cube, with two long extensions on either side, each formed from four protomers assembled into tetrameric coiled-coil regions, essentially as described by (Noone et al., 2022; doi:10.1073/pnas.2208144119). From crystallography and cryo-EM data, we identified a network of inter-protomer salt bridges that facilitate the assembly of the octamer. Small angle X-ray scattering (SAXS) validated our model for the octameric protein, including the analysis of two PTX3 constructs: a tetrameric ‘Half-PTX3’ and a construct missing the 24 N-terminal residues (Δ1–24_PTX3). SAXS determined a length of ∼520 Å for PTX3 and, combined with 3D variability analysis of cryo-EM data, defined the flexibility of the N-terminal extensions. Biophysical analyses revealed that the prototypical heavy chain HC1 does not interact with PTX3 at pH 7.4, consistent with our previous studies showing that, at this pH, PTX3 only associates with HC•HA complexes if they are formed in its presence. However, PTX3 binds to HC1 at acidic pH, and can also be incorporated into pre-formed HC•HA complexes under these conditions. This provides a novel mechanism for the regulation of PTX3-mediated HA crosslinking (e.g., during inflammation), likely mediated by a pH-dependent conformational change in HC1. The PTX3 octamer was found to associate simultaneously with up to eight HC1 molecules and, thus, has the potential to form a major crosslinking node within HC•HA matrices, i.e., where the physical and biochemical properties of resulting matrices could be tuned by the HC/PTX3 composition.
pentaxin -3 （PTX3）是一种八聚体蛋白，由八种相同的原体组成，在生殖生物学、先天免疫和癌症中具有多种功能。PTX3与大多糖透明质酸（HA）相互作用，而α-抑制剂（i -α-i）蛋白聚糖家族的重链（HC）共价附着于大多糖透明质酸（HA）上，在HC•HA复合物的（非共价）交联中起关键作用。这些相互作用稳定了积云基质，对哺乳动物的排卵和受精至关重要，并且在病毒性肺部感染的背景下也涉及致病性基质的形成。为了更好地理解PTX3的生理和病理作用，我们分析了PTX3的四级结构如何通过与hc的相互作用支持HA交联。x射线晶体学、低温电子显微镜（cryo-EM）和AlphaFold预测模型的结合显示，PTX3八聚体的c端戊烷素结构域排列在一个中心立方体中，两侧有两个长延伸，每个延伸由四个原聚体组装成四聚体卷曲线圈区域形成，基本上与(Noone等人，2022；doi: 10.1073 / pnas.2208144119)。从晶体学和低温电镜数据中，我们发现了一个促进八聚体组装的原聚体间盐桥网络。小角度x射线散射（SAXS）验证了我们的八聚体蛋白模型，包括对两种PTX3结构的分析：四聚体“半PTX3”和缺失24个n端残基的结构（Δ1-24-PTX3）。SAXS确定PTX3的长度为~ 520 Å，并结合cryo-EM数据的3D变异性分析，定义了n端扩展的灵活性。生物物理分析显示，在pH值7.4时，原型重链HC1不与PTX3相互作用，这与我们之前的研究结果一致，在该pH下，PTX3仅与HC•HA复合物结合，如果它们在其存在下形成。然而，PTX3在酸性pH下与HC1结合，并且在这些条件下也可以并入预形成的HC•HA配合物中。这为ptx3介导的HA交联调控提供了一种新的机制（例如，在炎症期间），可能是由HC1中ph依赖性构象变化介导的。PTX3八聚体被发现同时与多达8个HC1分子结合，因此，有可能在HC•HA基质中形成一个主要的交联节点，即，由此产生的基质的物理和生化特性可以通过HC/PTX3组成来调节。
{"title":"The structural organisation of pentraxin-3 and its interactions with heavy chains of inter-α-inhibitor regulate crosslinking of the hyaluronan matrix","authors":"Anokhi Shah ,&nbsp;Xiaoli Zhang ,&nbsp;Matthew Snee ,&nbsp;Michael P. Lockhart-Cairns ,&nbsp;Colin W. Levy ,&nbsp;Thomas A. Jowitt ,&nbsp;Holly L. Birchenough ,&nbsp;Louisa Dean ,&nbsp;Richard Collins ,&nbsp;Rebecca J. Dodd ,&nbsp;Abigail R.E. Roberts ,&nbsp;Jan J. Enghild ,&nbsp;Alberto Mantovani ,&nbsp;Juan Fontana ,&nbsp;Clair Baldock ,&nbsp;Antonio Inforzato ,&nbsp;Ralf P. Richter ,&nbsp;Anthony J. Day","doi":"10.1016/j.matbio.2025.01.002","DOIUrl":"10.1016/j.matbio.2025.01.002","url":null,"abstract":"<div><div>Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large polysaccharide hyaluronan (HA) to which heavy chains (HCs) of the inter-α-inhibitor (IαI) family of proteoglycans are covalently attached, playing a key role in the (non-covalent) crosslinking of HC•HA complexes. These interactions stabilise the cumulus matrix, essential for ovulation and fertilisation in mammals, and are also implicated in the formation of pathogenic matrices in the context of viral lung infections. To better understand the physiological and pathological roles of PTX3 we have analysed how its quaternary structure underpins HA crosslinking via its interactions with HCs. A combination of X-ray crystallography, cryo-electron microscopy (cryo-EM) and AlphaFold predictive modelling revealed that the C-terminal pentraxin domains of the PTX3 octamer are arranged in a central cube, with two long extensions on either side, each formed from four protomers assembled into tetrameric coiled-coil regions, essentially as described by (Noone <em>et al</em>., 2022; doi:10.1073/pnas.2208144119). From crystallography and cryo-EM data, we identified a network of inter-protomer salt bridges that facilitate the assembly of the octamer. Small angle X-ray scattering (SAXS) validated our model for the octameric protein, including the analysis of two PTX3 constructs: a tetrameric ‘Half-PTX3’ and a construct missing the 24 N-terminal residues (Δ1–24_PTX3). SAXS determined a length of ∼520 Å for PTX3 and, combined with 3D variability analysis of cryo-EM data, defined the flexibility of the N-terminal extensions. Biophysical analyses revealed that the prototypical heavy chain HC1 does not interact with PTX3 at pH 7.4, consistent with our previous studies showing that, at this pH, PTX3 only associates with HC•HA complexes if they are formed in its presence. However, PTX3 binds to HC1 at acidic pH, and can also be incorporated into pre-formed HC•HA complexes under these conditions. This provides a novel mechanism for the regulation of PTX3-mediated HA crosslinking (e.g., during inflammation), likely mediated by a pH-dependent conformational change in HC1. The PTX3 octamer was found to associate simultaneously with up to eight HC1 molecules and, thus, has the potential to form a major crosslinking node within HC•HA matrices, i.e., where the physical and biochemical properties of resulting matrices could be tuned by the HC/PTX3 composition.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 52-68"},"PeriodicalIF":4.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015211","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}
引用次数: 0
Neurocan regulates axon initial segment organization and neuronal activity Neurocan调节轴突初始段组织和神经元活动。
IF 4.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-07 DOI: 10.1016/j.matbio.2025.01.001
David Baidoe-Ansah , Hadi Mirzapourdelavar , Stepan Aleshin , Björn Hendrik Schott , Constanze Seidenbecher , Rahul Kaushik , Alexander Dityatev
The neural extracellular matrix (ECM) accumulates in the form of perineuronal nets (PNNs), particularly around fast-spiking GABAergic interneurons in the cortex and hippocampus, but also around synapses and in association with the axon initial segments (AIS) and nodes of Ranvier. Increasing evidence highlights the role of Neurocan (Ncan), a brain-specific component of ECM, in the pathophysiology of neuropsychiatric disorders like bipolar disorder and schizophrenia. Ncan localizes at PNNs, perisynaptically, and at the nodes of Ranvier and the AIS, highlighting its potential role in regulating axonal excitability. Here, we used knockdown and knockout approaches in mouse primary cortical neurons in combination with immunocytochemistry, Western blotting and electrophysiological techniques to characterize the role of Ncan in the organization of PNNs and AISs and regulation of neuronal activity. We found that reduced Ncan levels led to remodeling of PNNs around neurons via upregulation of aggrecan mRNA and protein levels, increased expression of activity-dependent c-Fos and FosB genes and elevated spontaneous synaptic activity. The latter correlated with increased levels of ankyrin-G in the AIS, particularly in excitatory neurons, and with the elevated expression of Nav1.6 channels. Our results suggest that Ncan regulates the expression of key proteins in PNNs and AISs and provide new insights into its role in fine-tuning neuronal functions.
神经细胞外基质（ECM）以神经元周围网（PNNs）的形式积累，特别是在皮层和海马的快速峰值gaba能中间神经元周围，但也在突触周围以及与轴突初始段（AIS）和Ranvier节点相关。越来越多的证据强调了神经can （Ncan）在双相情感障碍和精神分裂症等神经精神疾病的病理生理学中的作用，神经can是ECM的一种脑特异性成分。Ncan定位于pnn，突触周围，Ranvier和AIS节点，突出了其在调节轴突兴奋性中的潜在作用。本研究采用敲除和敲除小鼠原代皮质神经元的方法，结合免疫细胞化学、western blotting和电生理技术来表征Ncan在pnn和ais的组织以及神经元活性上调中的作用。我们发现，Ncan水平的降低通过Aggrecan mRNA和蛋白水平的上调、活性依赖性c-Fos和FosB基因的表达增加以及自发突触活性的升高，导致神经元周围pnn的重塑。后者与AIS中锚定蛋白g水平升高，特别是兴奋性神经元中锚定蛋白g水平升高以及Nav1.6通道表达升高相关。我们的研究结果表明，Ncan调节pnn和ais中关键蛋白的表达，并为其在微调神经元功能中的作用提供了新的见解。
{"title":"Neurocan regulates axon initial segment organization and neuronal activity","authors":"David Baidoe-Ansah ,&nbsp;Hadi Mirzapourdelavar ,&nbsp;Stepan Aleshin ,&nbsp;Björn Hendrik Schott ,&nbsp;Constanze Seidenbecher ,&nbsp;Rahul Kaushik ,&nbsp;Alexander Dityatev","doi":"10.1016/j.matbio.2025.01.001","DOIUrl":"10.1016/j.matbio.2025.01.001","url":null,"abstract":"<div><div>The neural extracellular matrix (ECM) accumulates in the form of perineuronal nets (PNNs), particularly around fast-spiking GABAergic interneurons in the cortex and hippocampus, but also around synapses and in association with the axon initial segments (AIS) and nodes of Ranvier. Increasing evidence highlights the role of Neurocan (Ncan), a brain-specific component of ECM, in the pathophysiology of neuropsychiatric disorders like bipolar disorder and schizophrenia. Ncan localizes at PNNs, perisynaptically, and at the nodes of Ranvier and the AIS, highlighting its potential role in regulating axonal excitability. Here, we used knockdown and knockout approaches in mouse primary cortical neurons in combination with immunocytochemistry, Western blotting and electrophysiological techniques to characterize the role of Ncan in the organization of PNNs and AISs and regulation of neuronal activity. We found that reduced Ncan levels led to remodeling of PNNs around neurons via upregulation of aggrecan mRNA and protein levels, increased expression of activity-dependent c-Fos and FosB genes and elevated spontaneous synaptic activity. The latter correlated with increased levels of ankyrin-G in the AIS, particularly in excitatory neurons, and with the elevated expression of Na<sub>v</sub>1.6 channels. Our results suggest that Ncan regulates the expression of key proteins in PNNs and AISs and provide new insights into its role in fine-tuning neuronal functions.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 22-35"},"PeriodicalIF":4.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957983","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}
引用次数: 0
FGF and TGF-β growth factor isoform modulation of human gingival and periodontal ligament fibroblast wound healing phenotype FGF和TGF-β生长因子亚型对人牙龈和牙周韧带成纤维细胞伤口愈合表型的调节。
IF 4.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-03 DOI: 10.1016/j.matbio.2024.12.011
Chengyu Guo , Amin S. Rizkalla , Douglas W. Hamilton
Release of growth factors in the tissue microenvironment is a critical process in the repair and regeneration of periodontal tissues, regulating fibroblast behavior and phenotype. As a result of the complex architecture of the periodontium, distinct fibroblast populations in the periodontal ligament and gingival connective tissue exist in close proximity. Growth factor therapies for periodontal regeneration have gained traction, but quantification of their effects on multiple different fibroblast populations that are required for repair has been poorly investigated. In this study, we examined the effects of TGF-β1, TGF-β3, FGF-2, and FGF-9 on human gingival fibroblasts (hGF) and human periodontal ligament cells (hPDL), as well as the combined effects of TGF-β3 and FGF-2. We show that FGF-2 enhances cell migration while TGF-β1 and TGF-β3 promotes matrix production, and TGF-β1 promotes fibroblast to myofibroblast transition. Interestingly, the combination of TGF-β3 and FGF-2, acting through both p-SMAD3 and p-ERK pathways, mitigates the inhibitory effects of TGF-β3 on migration in hPDL cells, suggesting synergistic and complimentary effects of FGF-2 and TGF-β3. Additionally, fibronectin production in hGF increased when treated with the combined TGF-β3+FGF-2 compared to FGF-2 alone, indicating that the effects of TGF-β3 in promoting extracellular matrix production are still active in the combined treatment condition. Finally, our study highlights that FGF-9 did not influence migration, α-SMA expression, or extracellular matrix production in either cell type, emphasizing the unique roles of specific growth factors in cellular responses. The synergistic effects observed with combined TGF-β3 and FGF-2 treatments present promising avenues for further research and clinical advancements in regenerative medicine.
组织微环境中生长因子的释放是牙周组织修复和再生、调节成纤维细胞行为和表型的关键过程。由于牙周组织结构复杂，在牙周韧带和牙龈结缔组织中存在着不同的成纤维细胞群。生长因子治疗牙周再生已经获得了广泛的关注，但是对其对修复所需的多种不同成纤维细胞群体的影响的量化研究却很少。本研究考察了TGF-β1、TGF-β3、FGF-2和FGF-9对人牙龈成纤维细胞（hGF）和人牙周韧带细胞（hPDL）的影响，以及TGF-β3和FGF-2的联合作用。我们发现FGF-2促进细胞迁移，TGF-β1和TGF-β3促进基质生成，TGF-β1促进成纤维细胞向肌成纤维细胞转变。有趣的是，TGF-β3和FGF-2联合作用，通过p-SMAD3和p-ERK途径，减轻了TGF-β3对hPDL细胞迁移的抑制作用，提示FGF-2和TGF-β3具有协同和互补作用。此外，TGF-β3+FGF-2联合治疗hGF比单独治疗FGF-2时，hGF中纤维连接蛋白的生成增加，表明TGF-β3促进细胞外基质生成的作用在联合治疗条件下仍然活跃。最后，我们的研究强调了FGF-9在两种细胞类型中都不影响迁移、α-SMA表达或细胞外基质的产生，强调了特定生长因子在细胞反应中的独特作用。TGF-β3和FGF-2联合治疗的协同效应为再生医学的进一步研究和临床进展提供了有希望的途径。
{"title":"FGF and TGF-β growth factor isoform modulation of human gingival and periodontal ligament fibroblast wound healing phenotype","authors":"Chengyu Guo ,&nbsp;Amin S. Rizkalla ,&nbsp;Douglas W. Hamilton","doi":"10.1016/j.matbio.2024.12.011","DOIUrl":"10.1016/j.matbio.2024.12.011","url":null,"abstract":"<div><div>Release of growth factors in the tissue microenvironment is a critical process in the repair and regeneration of periodontal tissues, regulating fibroblast behavior and phenotype. As a result of the complex architecture of the periodontium, distinct fibroblast populations in the periodontal ligament and gingival connective tissue exist in close proximity. Growth factor therapies for periodontal regeneration have gained traction, but quantification of their effects on multiple different fibroblast populations that are required for repair has been poorly investigated. In this study, we examined the effects of TGF-β1, TGF-β3, FGF-2, and FGF-9 on human gingival fibroblasts (hGF) and human periodontal ligament cells (hPDL), as well as the combined effects of TGF-β3 and FGF-2. We show that FGF-2 enhances cell migration while TGF-β1 and TGF-β3 promotes matrix production, and TGF-β1 promotes fibroblast to myofibroblast transition. Interestingly, the combination of TGF-β3 and FGF-2, acting through both p-SMAD3 and p-ERK pathways, mitigates the inhibitory effects of TGF-β3 on migration in hPDL cells, suggesting synergistic and complimentary effects of FGF-2 and TGF-β3. Additionally, fibronectin production in hGF increased when treated with the combined TGF-β3+FGF-2 compared to FGF-2 alone, indicating that the effects of TGF-β3 in promoting extracellular matrix production are still active in the combined treatment condition. Finally, our study highlights that FGF-9 did not influence migration, α-SMA expression, or extracellular matrix production in either cell type, emphasizing the unique roles of specific growth factors in cellular responses. The synergistic effects observed with combined TGF-β3 and FGF-2 treatments present promising avenues for further research and clinical advancements in regenerative medicine.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 9-21"},"PeriodicalIF":4.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933403","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}
引用次数: 0
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-01
{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"139 ","pages":"Pages 49-60"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147141555","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}
引用次数: 0
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-01
{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"140 ","pages":"Pages 27-42"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146916784","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}
引用次数: 0
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matrix Biology
Pub Date : 2025-01-01
{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"141 ","pages":"Pages 101-113"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146970848","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}
引用次数: 0
首页 上一页
类型
全部 化学•材料 生命科学 医学 物理 工程技术 环境•农林 材料科学 地球科学 法学 管理学 化学 环境科学与生态学 计算机科学 教育学 经济学 农林科学 人文科学 生物学 数学 物理与天体物理 心理学 综合性期刊 其他 工业工程 理学 历史学 农学 文学 信息工程
数据库
全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley
期刊
Matrix Biology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
﹀
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整，为了账户安全，请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号：604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们：info@booksci.cn
Book学术提供免费学术资源搜索服务，方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1