Matrix Biology最新文献

{"title":"Impact of vascular Ehlers-Danlos Syndrome-associated Gly substitutions on structure, function, and mechanics using bacterial collagen","authors":"Sonal Gahlawat ,&nbsp;Jan Siess ,&nbsp;Natalie Losada ,&nbsp;Jennifer Timm ,&nbsp;Vikas Nanda ,&nbsp;David I. Shreiber","doi":"10.1016/j.matbio.2024.12.002","DOIUrl":"10.1016/j.matbio.2024.12.002","url":null,"abstract":"<div><div>Vascular Ehlers-Danlos syndrome (vEDS) arises from mutations in collagen-III, a major structural component of the extracellular matrix (ECM) in vascularized tissues, including blood vessels. Fibrillar collagens form a triple-helix that is characterized by a canonical (Gly-X-Y)_n sequence. The substitution of another amino acid for Gly within this conserved repeating sequence is associated with several hereditary connective tissue disorders, including vEDS. The clinical severity of vEDS depends on the identity of the substituted amino acid and its location. In this study, we engineered recombinant bacterial collagen-like proteins (CLPs) with previously reported Gly→X (X=Ser or Arg) vEDS substitutions within the integrin-binding site. Employing a combination of biophysical techniques, enzymatic digestion assays, integrin binding affinity assays, and computational modeling, we assessed the impact of Gly→X substitutions on structure, stability, function, and mechanical properties. While constructs with Ser or Arg substitutions maintained a triple-helix structure, Arg substitution significantly reduced global thermal stability, heightened susceptibility to trypsin digestion, and altered integrin α2-inserted (α2I) domain binding. Molecular dynamics (MD) simulations also demonstrated distinct effects of different Gly substitutions on the triple-helix structure - Arg substitutions induced notable bulging at the substitution site and disrupted interchain hydrogen bonds compared to Ser substitutions. Additionally, steered MD simulations revealed that Arg substitution led to a significant decrease in the Young's modulus of the triple-helix. Bacterial CLPs have proved to be a powerful model for studying the underlying mechanisms of vEDS-causing mutations in collagen-III. Serine and arginine substitutions differentially perturb cell-matrix interactions and ECM in a manner consistent with clinical vEDS severity.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 87-98"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AGEing of collagen: The effects of glycation on collagen’s stability, mechanics and assembly","authors":"Daniel Sloseris,&nbsp;Nancy R. Forde","doi":"10.1016/j.matbio.2024.12.007","DOIUrl":"10.1016/j.matbio.2024.12.007","url":null,"abstract":"<div><div>Advanced Glycation End Products (AGEs) are the end result of the irreversible, non-enzymatic glycation of proteins by reducing sugars. These chemical modifications accumulate with age and have been associated with various age-related and diabetic complications. AGEs predominantly accumulate on proteins with slow turnover rates, of which collagen is a prime example. Glycation has been associated with tissue stiffening and reduced collagen fibril remodelling. In this study, we investigate the effects of glycation on the stability of type I collagen, its molecular-level mechanics and its ability to perform its physiological role of self-assembly. Collagen AGEing is induced <em>in vitro</em> by incubation with ribose. We confirm and assess glycation using fluorescence measurements and changes in collagen’s electrophoretic mobility. Susceptibility to trypsin digestion and circular dichroism (CD) spectroscopy are used to probe changes in collagen’s triple helical stability, revealing decreased stability due to glycation. Atomic Force Microscopy (AFM) imaging is used to quantify how AGEing affects collagen flexibility, where we find molecular-scale stiffening. Finally we use microscopy to show that glycated collagen molecules are unable to self-assemble into fibrils. These findings shed light on the molecular mechanisms underlying AGE-induced tissue changes, offering insight into how glycation modifies protein structure and stability.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"135 ","pages":"Pages 153-160"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"George R. Martin: Pioneering matrix biologist","authors":"Andrew Leask ,&nbsp;Richard J. Stratton","doi":"10.1016/j.matbio.2025.01.007","DOIUrl":"10.1016/j.matbio.2025.01.007","url":null,"abstract":"","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"136 ","pages":"Pages 69-70"},"PeriodicalIF":4.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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}

{"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}

{"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}

{"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":"&lt;div&gt;&lt;div&gt;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.&lt;/div&gt;&lt;div&gt;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 (&lt;em&gt;Fbln5&lt;sup&gt;-/-&lt;/sup&gt;&lt;/em&gt;) mouse carotid arteries. Biomechanical testing demonstrated that &lt;em&gt;Fbln5&lt;sup&gt;-/-&lt;/sup&gt;&lt;/em&gt; arteries under disturbed flow approximate the stiffness ratio of diseased human arteries, and the ECs in these &lt;em&gt;Fbln5&lt;sup&gt;-/-&lt;/sup&gt;&lt;/em&gt; arteries underwent rapid reprogramming via endothelial to mesenchymal transition (EndMT). Under atherogenic conditions, disturbed flow &lt;em&gt;Fbln5&lt;sup&gt;-/-&lt;/sup&gt;&lt;/em&gt; arteries developed more vulnerable plaques than the wild type (WT) mouse arteries. Connective tissue growth factor/cellular communication network factor 2 (&lt;em&gt;Ctgf&lt;/em&gt;/&lt;em&gt;Ccn2&lt;/em&gt;) was upregulated in vivo in ECs with aging, with stiffening in the &lt;em&gt;Fbln5&lt;/em&gt;&lt;sup&gt;-/-&lt;/sup&gt; 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 &lt;em&gt;Ctgf&lt;/em&gt; knockout (&lt;em&gt;Ctgf&lt;sup&gt;ecko&lt;/sup&gt;&lt;/em&gt;). We identified that carotid arteries under disturbed flow and atherogenic conditions in male &lt;em&gt;Ctgf&lt;sup&gt;ecko&lt;/sup&gt;&lt;/em&gt;, but not female, mice had decreased plaque area compared to WT control mice. We then tested the &lt;em&gt;Ctgf&lt;/em&gt; expression in the carotid endothelium exposed to disturbed or stable flow in WT and &lt;em&gt;Fbln5&lt;sup&gt;-/-&lt;/sup&gt;&lt;/em&gt; mice. Here we found that under disturbed flow male mice had greater &lt;em&gt;Ctgf&lt;/em&gt; expression than female mice.&lt;/div&gt;&lt;div&gt;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.&lt;/","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}

{"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}

{"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_v1.6 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}

{"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}