Pub Date : 2025-04-01Epub Date: 2025-02-06DOI: 10.1016/j.matbio.2025.02.001
Alexander Nyström
The skin, as a barrier organ meeting constant mechanical challenges, is equipped with multiple adhesive structures that collectively support resilient, yet flexible attachment of its epithelium –the epidermis to its mesenchyme – the dermis. One such structure is the collagen VII-composed anchoring fibril, which provides firm anchorage of the epidermal basement membrane to the underlying interstitial extracellular matrix. Blistering and wider tissue fragility in the genetic disease dystrophic epidermolysis bullosa (DEB) caused by collagen VII deficiency illustrate the essential function of collagen VII in supporting skin integrity. DEB is also a progressive inflammatory fibrotic disease with multi-organ involvement, indicating that collagen VII has broader functions than simply providing epithelial anchorage. This review explores the reciprocal relationship between collagen VII biology and DEB pathophysiology. A deeper understanding of collagen VII biology – spanning its synthesis, assembly into suprastructures, and regulatory roles – enhances our understanding of DEB. Conversely, detailed insights into DEB through analysis of disease progression or therapeutic interventions offer valuable information on the broader tissue and organismal roles of collagen VII in maintaining homeostasis. This review focuses on such knowledge exchange in advancing our understanding of collagen VII, the extracellular matrix in general, and inspiring potential strategies for treatment of DEB. Importantly, in a broader sense, the discussed themes are applicable to other conditions driven by compromised extracellular matrix instruction and integrity, leading to progressive damage and inflammation.
{"title":"Dystrophic epidermolysis bullosa - From biochemistry to interventions","authors":"Alexander Nyström","doi":"10.1016/j.matbio.2025.02.001","DOIUrl":"10.1016/j.matbio.2025.02.001","url":null,"abstract":"<div><div>The skin, as a barrier organ meeting constant mechanical challenges, is equipped with multiple adhesive structures that collectively support resilient, yet flexible attachment of its epithelium –the epidermis to its mesenchyme – the dermis. One such structure is the collagen VII-composed anchoring fibril, which provides firm anchorage of the epidermal basement membrane to the underlying interstitial extracellular matrix. Blistering and wider tissue fragility in the genetic disease dystrophic epidermolysis bullosa (DEB) caused by collagen VII deficiency illustrate the essential function of collagen VII in supporting skin integrity. DEB is also a progressive inflammatory fibrotic disease with multi-organ involvement, indicating that collagen VII has broader functions than simply providing epithelial anchorage. This review explores the reciprocal relationship between collagen VII biology and DEB pathophysiology. A deeper understanding of collagen VII biology – spanning its synthesis, assembly into suprastructures, and regulatory roles – enhances our understanding of DEB. Conversely, detailed insights into DEB through analysis of disease progression or therapeutic interventions offer valuable information on the broader tissue and organismal roles of collagen VII in maintaining homeostasis. This review focuses on such knowledge exchange in advancing our understanding of collagen VII, the extracellular matrix in general, and inspiring potential strategies for treatment of DEB. Importantly, in a broader sense, the discussed themes are applicable to other conditions driven by compromised extracellular matrix instruction and integrity, leading to progressive damage and inflammation.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 111-126"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143369736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2025-01-23DOI: 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.
{"title":"Spatial localization of collagen hydroxylated proline site variation as an ancestral trait in the breast cancer microenvironment","authors":"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","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":"2025-04-01","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}
Pub Date : 2025-04-01Epub Date: 2025-01-17DOI: 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.
{"title":"CD45+/ Col I+ Fibrocytes: Major source of collagen in the fibrotic lung, but not in passaged fibroblast cultures","authors":"Charles F. Reese , Monika Gooz , Zoltan Hajdu , 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 (>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":"2025-04-01","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}
Pub Date : 2025-04-01Epub Date: 2025-01-17DOI: 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.
{"title":"Decoding the MMP14 integrin link: Key player in the secretome landscape","authors":"Stephan Niland, 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":"2025-04-01","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}
Pub Date : 2025-04-01Epub Date: 2025-01-13DOI: 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.
{"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 , 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","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":"2025-04-01","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}
Pub Date : 2025-04-01Epub Date: 2025-01-03DOI: 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.
{"title":"FGF and TGF-β growth factor isoform modulation of human gingival and periodontal ligament fibroblast wound healing phenotype","authors":"Chengyu Guo , Amin S. Rizkalla , 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":"2025-04-01","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}
Pub Date : 2025-04-01Epub Date: 2024-12-26DOI: 10.1016/j.matbio.2024.12.010
Semanti Ray , Emily Huang , Megan R McMullen , Samreen Jatana , Carol de la Motte , Laura E Nagy
Obesity is a growing concern in the US and world-wide, associated with an increased risk for several cardiometabolic diseases, including metabolic associated steatotic liver disease (MASLD). Currently, therapeutic interventions to prevent and/or treat MASLD are limited, and research is needed to identify new therapeutic targets. The specific-sized 35 kDa fragment of hyaluronan (HA35), has gut protective and anti-inflammatory properties and a previous pilot clinical study reported it is well tolerated in healthy individuals. Here we tested the hypothesis that HA35 treatment ameliorates high fat diet-induced liver injury. Five-week-old male C57BL/6 J mice were allowed ad lib access to control chow or high fat fructose and cholesterol (FFC) diet over a period of 12 weeks. HA35 was administered at 15mg/kg via oral gavage on the last 6 days of the study as a therapeutic intervention. Mice on FFC diet-gained more body weight compared to those on chow diet, with final body weights ranging from 30.8 to 45.6 g. FFC diet caused hepatocyte injury, increased expression of inflammatory cytokine/chemokine mRNA, as well as indicators of liver fibrosis. When mice were stratified based on their final body weight, only mice <40 g were protected by treatment with HA35. In this group, treatment with HA35 also restored tight junction integrity in the colon and increased expression of α -defensins in the small intestine. Taken together the data suggests that HA35 is an effective therapeutic in ameliorating high fat diet-induced liver inflammation and fibrosis in moderately obese, but not severe, conditions.
{"title":"35k Da specific-sized hyaluronan ameliorates high-fat diet-induced liver injury in murine model of moderate obesity","authors":"Semanti Ray , Emily Huang , Megan R McMullen , Samreen Jatana , Carol de la Motte , Laura E Nagy","doi":"10.1016/j.matbio.2024.12.010","DOIUrl":"10.1016/j.matbio.2024.12.010","url":null,"abstract":"<div><div>Obesity is a growing concern in the US and world-wide, associated with an increased risk for several cardiometabolic diseases, including metabolic associated steatotic liver disease (MASLD). Currently, therapeutic interventions to prevent and/or treat MASLD are limited, and research is needed to identify new therapeutic targets. The specific-sized 35 kDa fragment of hyaluronan (HA35), has gut protective and anti-inflammatory properties and a previous pilot clinical study reported it is well tolerated in healthy individuals. Here we tested the hypothesis that HA35 treatment ameliorates high fat diet-induced liver injury. Five-week-old male C57BL/6 J mice were allowed <em>ad lib</em> access to control chow or high fat fructose and cholesterol (FFC) diet over a period of 12 weeks. HA35 was administered at 15mg/kg via oral gavage on the last 6 days of the study as a therapeutic intervention. Mice on FFC diet-gained more body weight compared to those on chow diet, with final body weights ranging from 30.8 to 45.6 g. FFC diet caused hepatocyte injury, increased expression of inflammatory cytokine/chemokine mRNA, as well as indicators of liver fibrosis. When mice were stratified based on their final body weight, only mice <40 g were protected by treatment with HA35. In this group, treatment with HA35 also restored tight junction integrity in the colon and increased expression of α -defensins in the small intestine. Taken together the data suggests that HA35 is an effective therapeutic in ameliorating high fat diet-induced liver inflammation and fibrosis in moderately obese, but not severe, conditions.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 1-8"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2025-01-07DOI: 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.
{"title":"Neurocan regulates axon initial segment organization and neuronal activity","authors":"David Baidoe-Ansah , Hadi Mirzapourdelavar , Stepan Aleshin , Björn Hendrik Schott , Constanze Seidenbecher , Rahul Kaushik , 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":"2025-04-01","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}
Pub Date : 2025-02-01Epub 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":"2025-02-01","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}
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