Matrix Biology Plus最新文献

{"title":"Targeted conditional collagen XII deletion alters tendon function","authors":"Ashley Fung ,&nbsp;Mei Sun ,&nbsp;Louis J. Soslowsky ,&nbsp;David E. Birk","doi":"10.1016/j.mbplus.2022.100123","DOIUrl":"10.1016/j.mbplus.2022.100123","url":null,"abstract":"<div><p>Collagen XII is a fibril-associated collagen with interrupted triple helices (FACIT). This non-fibrillar collagen is a homotrimer composed of three α1(XII) chains assembled into a collagenous molecule with a C terminal collagenous domain and a large N terminal non-collagenous domain. During tendon development and growth, collagen XII is broadly expressed throughout the extracellular matrix and enriched pericellularly around tenocytes. Tendons in a global <em>Col12a1</em>^<em>-/-</em> knockout model demonstrated disrupted fibril and fiber structure and disordered tenocyte organization, highlighting the critical regulatory roles of collagen XII in determining tendon structure and function. However, muscle and bone also are affected in the collagen XII knockout model. Therefore, secondary effects on tendon due to involvement of bone and muscle may occur in the global knockout. The global knockout does not allow the definition of intrinsic mechanisms involving collagen XII in tendon versus extrinsic roles involving muscle and bone. To address this limitation, we created and characterized a conditional <em>Col12a1</em>-null mouse model to permit the spatial and temporal manipulation of <em>Col12a1</em> expression. Collagen XII knockout was targeted to tendons by breeding conditional <em>Col12a1</em>^{<em>flox/flox</em>} mice with Scleraxis-Cre (<em>Scx-</em>Cre) mice to yield a tendon-specific <em>Col12a1</em>-null mouse line, <em>Col12a1</em>^{<em>Δten/Δten</em>}. Both mRNA and protein expression in <em>Col12a1</em>^{<em>Δten/Δten</em>} mice decreased to near baseline levels in flexor digitorum longus tendons (FDL). Collagen XII immuno-localization revealed an absence of reactivity in the tendon proper, but there was reactivity in the cells of the surrounding peritenon. This supports a targeted knockout in tenocytes while peritenon cells from a non-tendon lineage were not targeted and retained collagen XII expression. The tendon-targeted, <em>Col12a1</em>^{<em>Δten/Δten</em>} <!-->mice had significantly reduced forelimb grip strength, altered gait and a significant decrease in biomechanical properties. While the observed decrease in tendon modulus suggests that differences in tendon material properties in the absence of <em>Col12a1</em> expression underlie the functional deficiencies. Together, these findings suggest an intrinsic role for collagen XII critical for development of a functional tendon.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"16 ","pages":"Article 100123"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/56/8d/main.PMC9597098.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9366343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular Matrix Profiling and Disease Modelling in Engineered Vascular Smooth Muscle Cell Tissues","authors":"Ella Reed ,&nbsp;Adam Fellows ,&nbsp;Ruifang Lu ,&nbsp;Marieke Rienks ,&nbsp;Lukas Schmidt ,&nbsp;Xiaoke Yin ,&nbsp;Elisa Duregotti ,&nbsp;Mona Brandt ,&nbsp;Susanne Krasemann ,&nbsp;Kristin Hartmann ,&nbsp;Javier Barallobre-Barreiro ,&nbsp;Owen Addison ,&nbsp;Friederike Cuello ,&nbsp;Arne Hansen ,&nbsp;Manuel Mayr","doi":"10.1016/j.mbplus.2022.100122","DOIUrl":"10.1016/j.mbplus.2022.100122","url":null,"abstract":"<div><p>Aortic smooth muscle cells (SMCs) have an intrinsic role in regulating vessel homeostasis and pathological remodelling. In two-dimensional (2D) cell culture formats, however, SMCs are not embedded in their physiological extracellular matrix (ECM) environment. To overcome the limitations of conventional 2D SMC cultures, we established a 3D <em>in vitro</em> model of engineered vascular smooth muscle cell tissues (EVTs). EVTs were casted from primary murine aortic SMCs by suspending a SMC-fibrin master mix between two flexible silicon-posts at day 0 before prolonged culture up to 14 days. Immunohistochemical analysis of EVT longitudinal sections demonstrated that SMCs were aligned, viable and secretory. Mass spectrometry-based proteomics analysis of murine EVT lysates was performed and identified 135 matrisome proteins. Proteoglycans, including the large aggregating proteoglycan versican, accumulated within EVTs by day 7 of culture. This was followed by the deposition of collagens, elastin-binding proteins and matrix regulators up to day 14 of culture. In contrast to 2D SMC controls, accumulation of versican occurred in parallel to an increase in versikine, a cleavage product mediated by proteases of the A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) family. Next, we tested the response of EVTs to stimulation with transforming growth factor beta-1 (TGFβ-1). EVTs contracted in response to TGFβ-1 stimulation with altered ECM composition. In contrast, treatment with the pharmacological activin-like kinase inhibitor (ALKi) SB 431542 suppressed ECM secretion. As a disease stimulus, we performed calcification assays. The ECM acts as a nidus for calcium phosphate deposition in the arterial wall. We compared the onset and extent of calcification in EVTs and 2D SMCs cultured under high calcium and phosphate conditions for 7 days. Calcified EVTs displayed increased tissue stiffness by up to 30 % compared to non-calcified controls. Unlike the rapid calcification of SMCs in 2D cultures, EVTs sustained expression of the calcification inhibitor matrix Gla protein and allowed for better discrimination of the calcification propensity between independent biological replicates. In summary, EVTs are an intuitive and versatile model to investigate ECM synthesis and turnover by SMCs in a 3D environment. Unlike conventional 2D cultures, EVTs provide a more relevant pathophysiological model for retention of the nascent ECM produced by SMCs.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"16 ","pages":"Article 100122"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9526190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33487604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function","authors":"Danielle Pretorius ,&nbsp;Robert P. Richter ,&nbsp;Tanya Anand ,&nbsp;Jessica C. Cardenas ,&nbsp;Jillian R. Richter","doi":"10.1016/j.mbplus.2022.100121","DOIUrl":"10.1016/j.mbplus.2022.100121","url":null,"abstract":"<div><p>The glycocalyx attached to the apical surface of vascular endothelial cells is a rich network of proteoglycans, glycosaminoglycans, and glycoproteins with instrumental roles in vascular homeostasis. Given their molecular complexity and ability to interact with the intra- and extracellular environment, heparan sulfate proteoglycans uniquely contribute to the glycocalyx’s role in regulating endothelial permeability, mechanosignaling, and ligand recognition by cognate cell surface receptors. Much attention has recently been devoted to the enzymatic shedding of heparan sulfate proteoglycans from the endothelial glycocalyx and its impact on vascular function. However, other molecular modifications to heparan sulfate proteoglycans are possible and may have equal or complementary clinical significance. In this narrative review, we focus on putative mechanisms driving non-proteolytic changes in heparan sulfate proteoglycan expression and alterations in the sulfation of heparan sulfate side chains within the endothelial glycocalyx. We then discuss how these specific changes to the endothelial glycocalyx impact endothelial cell function and highlight therapeutic strategies to target or potentially reverse these pathologic changes.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"16 ","pages":"Article 100121"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/53/3a/main.PMC9494232.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33484981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrin α3 negative podocytes: A gene expression study","authors":"L.H. Frommherz ,&nbsp;S.B. Sayar ,&nbsp;Y. Wang ,&nbsp;L.K. Trefzer ,&nbsp;Y. He ,&nbsp;J. Leppert ,&nbsp;P. Eßer ,&nbsp;C. Has","doi":"10.1016/j.mbplus.2022.100119","DOIUrl":"10.1016/j.mbplus.2022.100119","url":null,"abstract":"<div><p>Integrin α3β1 is a cell adhesion receptor widely expressed in epithelial cells. Pathogenic variants in the gene encoding the integrin α3 subunit <em>ITGA3</em> lead to a syndrome including interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa (ILNEB). Renal involvement mainly consists of glomerular disease caused by loss of adhesion between podocytes and the glomerular basement membrane.</p><p>The aim of this study was to characterize the impact of loss of integrin α3 on human podocytes.</p><p><em>ITGA3</em> was stably knocked-out in the human podocyte cell line AB8/13, designated as Podo^A3−, and in human proximal tubule epithelial cell line HK2 using the targeted genome editing technique CRISPR/Cas9. Cell clones were characterized by Sanger sequencing, quantitative PCR, Western Blot and immunofluorescence staining. RNASeq of integrin α3 negative cells and controls was performed to identify differential gene expression patterns.</p><p>Differentiated Podo^A3− did not substantially change morphology and adhesion under standard culture conditions, but displayed significantly reduced spreading and adhesion when seed on laminin 511 in serum free medium. Gene expression studies demonstrated a distinct dysregulation of the adhesion network with downregulation of most integrin α3 interaction partners. In agreement with this, biological processes such as “extracellular matrix organization” and “cell differentiation” as well as KEGG pathways such as “ECM-receptor interaction”, “focal adhesion” and the “PI3K-Akt signaling pathway” were significantly downregulated in human podocytes lacking the integrin α3 subunit.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"16 ","pages":"Article 100119"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f8/d4/main.PMC9429797.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40350324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Periostin modulates extracellular matrix behavior in tendons","authors":"Kevin I. Rolnick ,&nbsp;Joshua A. Choe ,&nbsp;Ellen M. Leiferman ,&nbsp;Jaclyn Kondratko-Mittnacht ,&nbsp;Anna E.B. Clements ,&nbsp;Geoffrey S. Baer ,&nbsp;Peng Jiang ,&nbsp;Ray Vanderby ,&nbsp;Connie S. Chamberlain","doi":"10.1016/j.mbplus.2022.100124","DOIUrl":"10.1016/j.mbplus.2022.100124","url":null,"abstract":"<div><p>Periostin, originally named osteoblast-specific factor 2 (OSF-2) has been identified primarily in collagen rich, biomechanically active tissues where its role has been implicated in mechanisms to maintain the extracellular matrix (ECM), including collagen fibrillogenesis and crosslinking. It is well documented that periostin plays a role in wound healing and scar formation after injury, in part, by promoting cell proliferation, myofibroblast differentiation, and/or collagen fibrillogenesis. Given the significance of periostin in other scar forming models, we hypothesized that periostin will influence Achilles tendon healing by modulating ECM production. Therefore, the objective of this study was to elucidate the effects of periostin during Achilles tendon healing using periostin homozygous (<em>Postn</em>^−/−) and heterozygous (<em>Postn</em>^+/-) mouse models. A second experiment was included to further examine the influence of periostin on collagen composition and function using intact dorsal tail tendons. Overall, <em>Postn</em>^−/− and <em>Postn</em>^+/- Achilles tendons exhibited impaired healing as demonstrated by delayed wound closure, increased type III collagen production, decreased cell proliferation, and reduced tensile strength. Periostin ablation also reduced tensile strength and stiffness, and altered collagen fibril distribution in the intact dorsal tail tendons. Achilles tendon outcomes support our hypothesis that periostin influences healing, while tail tendon results indicate that periostin also affects ECM morphology and behavior in mouse tendons.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"16 ","pages":"Article 100124"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6e/02/main.PMC9673102.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40475368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Laminin α5_CD239_Spectrin is a candidate association that compensates the linkage between the basement membrane and cytoskeleton in skeletal muscle fibers","authors":"Yamato Kikkawa ,&nbsp;Masumi Matsunuma ,&nbsp;Ryuji Kan ,&nbsp;Yuji Yamada ,&nbsp;Keisuke Hamada ,&nbsp;Motoyoshi Nomizu ,&nbsp;Yoichi Negishi ,&nbsp;Shushi Nagamori ,&nbsp;Tatsushi Toda ,&nbsp;Minoru Tanaka ,&nbsp;Motoi Kanagawa","doi":"10.1016/j.mbplus.2022.100118","DOIUrl":"10.1016/j.mbplus.2022.100118","url":null,"abstract":"<div><p>The linkage between the basement membrane (BM) and cytoskeleton is crucial for muscle fiber stability and signal transduction. Mutations in the linkage molecules can cause various types of muscular dystrophies. The different severities and times of onset suggest that compensatory linkages occur at the sarcolemma. Cluster of differentiation 239 (CD239) binds to the α5 subunit of laminin-511 extracellularly and is connected to spectrin intracellularly, resulting in a linkage between the BM and cytoskeleton. In this study, we explored the linkage of laminin α5_CD239_spectrin in skeletal muscles. Although laminin α5, CD239, and spectrin were present in embryonic skeletal muscles, they disappeared in adult skeletal muscle tissues, except for the soleus and diaphragm. Laminin α5_CD239_spectrin was localized in the skeletal muscle tissues of Duchenne muscular dystrophy and congenital muscular dystrophy mouse models. The experimental regeneration of skeletal muscle increased the CD239-mediated linkage, indicating that it responds to regeneration, but not to genetic influence. Furthermore, <em>in silico</em> analysis showed that laminin α5_CD239_spectrin was upregulated by steroid therapy for muscular dystrophy. Therefore, CD239-mediated linkage may serve as a therapeutic target to prevent the progression of muscular dystrophy.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"15 ","pages":"Article 100118"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9382564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40414099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decorin knockdown is beneficial for aged tendons in the presence of biglycan expression","authors":"Zakary M. Beach ,&nbsp;Mihir S. Dekhne ,&nbsp;Ashley B. Rodriguez ,&nbsp;Stephanie N. Weiss ,&nbsp;Thomas H. Adams ,&nbsp;Sheila M. Adams ,&nbsp;Mei Sun ,&nbsp;David E. Birk ,&nbsp;Louis J. Soslowsky","doi":"10.1016/j.mbplus.2022.100114","DOIUrl":"10.1016/j.mbplus.2022.100114","url":null,"abstract":"<div><p>Decorin and biglycan are two major small leucine-rich proteoglycans (SLRPs) present in the tendon extracellular matrix that facilitate collagen fibrillogenesis, tissue turnover, and cell signal transduction. Previously, we demonstrated that knockout of decorin prevented the decline of tendon mechanical properties that are associated with aging. The objective of this study was to determine the effects of decorin and biglycan knockdown on tendon structure and mechanics in aged tendons using tamoxifen-inducible knockdown models. We hypothesized that the knockdown of decorin and compound knockdown of decorin and biglycan would prevent age-related declines in tendon mechanics and structure compared to biglycan knockdown and wild-type controls, and that these changes would be exacerbated as the tendons progress towards geriatric ages. To achieve this objective, we created tamoxifen-inducible mouse knockdown models to target decorin and biglycan gene inactivation without the abnormal tendon development associated with traditional knockout models. Knockdown of decorin led to increased midsubstance modulus and decreased stress relaxation in aged tendons. However, these changes were not sustained in the geriatric tendons. Knockdown in biglycan led to no changes in mechanics in the aged or geriatric tendons. Contrary to our hypothesis, the compound decorin/biglycan knockdown tendons did not resemble the decorin knockdown tendons, but resulted in increased viscoelastic properties in the aged and geriatric tendons. Structurally, knockdown of SLRPs, except for the 570d I-<em>Dcn</em>^<em>-/-</em><em>/Bgn</em>^<em>-/-</em> group, resulted in alterations to the collagen fibril diameter relative to wild-type controls. Overall, this study identified the differential roles of decorin and biglycan throughout tendon aging in the maintenance of tendon structural and mechanical properties and revealed that the compound decorin and biglycan knockdown phenotype did not resemble the single gene decorin or biglycan models and was detrimental to tendon properties throughout aging.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"15 ","pages":"Article 100114"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/92/62/main.PMC9270257.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9719594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the extracellular matrix transcriptome of cervical, endometrial, and uterine cancers","authors":"Carson J. Cook ,&nbsp;Andrew E. Miller ,&nbsp;Thomas H. Barker ,&nbsp;Yanming Di ,&nbsp;Kaitlin C. Fogg","doi":"10.1016/j.mbplus.2022.100117","DOIUrl":"10.1016/j.mbplus.2022.100117","url":null,"abstract":"<div><p>Increasingly, the matrisome, a set of proteins that form the core of the extracellular matrix (ECM) or are closely associated with it, has been demonstrated to play a key role in tumor progression. However, in the context of gynecological cancers, the matrisome has not been well characterized. A holistic, yet targeted, exploration of the tumor microenvironment is critical for better understanding the progression of gynecological cancers, identifying key biomarkers for cancer progression, establishing the role of gene expression in patient survival, and for assisting in the development of new targeted therapies. In this work, we explored the matrisome gene expression profiles of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS) using publicly available RNA-seq data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) portal. We hypothesized that the matrisomal expression patterns of CESC, UCEC, and UCS would be highly distinct with respect to genes which are differentially expressed and hold inferential significance with respect to tumor progression, patient survival, or both. Through a combination of statistical and machine learning analysis techniques, we identified sets of genes and gene networks which characterized each of the gynecological cancer cohorts. Our findings demonstrate that the matrisome is critical for characterizing gynecological cancers and transcriptomic mechanisms of cancer progression and outcome. Furthermore, while the goal of pan-cancer transcriptional analyses is often to highlight the shared attributes of these cancer types, we demonstrate that they are highly distinct diseases which require separate analysis, modeling, and treatment approaches. In future studies, matrisome genes and gene ontology terms that were identified as holding inferential significance for cancer stage and patient survival can be evaluated as potential drug targets and incorporated into <em>in vitro</em> models of disease.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"15 ","pages":"Article 100117"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/e4/main.PMC9309672.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40553590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic systems analysis identifies a novel mechanism contributing to shock in patients with endotheliopathy of trauma (EoT) involving thromboxane A2 and LTC4","authors":"Hanne H. Henriksen ,&nbsp;Igor Marín de Mas ,&nbsp;Helena Herand ,&nbsp;Joseph Krocker ,&nbsp;Charles E. Wade ,&nbsp;Pär I. Johansson","doi":"10.1016/j.mbplus.2022.100115","DOIUrl":"10.1016/j.mbplus.2022.100115","url":null,"abstract":"<div><h3>Purpose</h3><p>Endotheliopathy of trauma (EoT), as defined by circulating levels of syndecan-1 ≥ 40 ng/mL, has been reported to be associated with significantly increased transfusion requirements and a doubled 30-day mortality. Increased shedding of the glycocalyx points toward the endothelial cell membrane composition as important for the clinical outcome being the rationale for this study.</p></div><div><h3>Results</h3><p>The plasma metabolome of 95 severely injured trauma patients was investigated by mass spectrometry, and patients with EoT vs. non-EoT were compared by partial least square-discriminant analysis, identifying succinic acid as the top metabolite to differentiate EoT and non-EoT patients (VIP score = 3). EoT and non-EoT patients’ metabolic flux profile was inferred by integrating the corresponding plasma metabolome data into a genome-scale metabolic network reconstruction analysis and performing a functional study of the metabolic capabilities of each group. Model predictions showed a decrease in cholesterol metabolism secondary to impaired mevalonate synthesis in EoT compared to non-EoT patients. Intracellular task analysis indicated decreased synthesis of thromboxanA2 and leukotrienes, as well as a lower carnitine palmitoyltransferase I activity in EoT compared to non-EoT patients. Sensitivity analysis also showed a significantly high dependence of eicosanoid-associated metabolic tasks on alpha-linolenic acid as unique to EoT patients.</p></div><div><h3>Conclusions</h3><p>Model-driven analysis of the endothelial cells’ metabolism identified potential novel targets as impaired thromboxane A2 and leukotriene synthesis in EoT patients when compared to non-EoT patients. Reduced thromboxane A2 and leukotriene availability in the microvasculature impairs vasoconstriction ability and may thus contribute to shock in EoT patients. These findings are supported by extensive scientific literature; however, further investigations are required on these findings.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"15 ","pages":"Article 100115"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/14/main.PMC9260291.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10056395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac fibroblast sub-types in vitro reflect pathological cardiac remodeling in vivo","authors":"Kate Møller Herum ,&nbsp;Guangzheng Weng ,&nbsp;Konstantin Kahnert ,&nbsp;Rebekah Waikel ,&nbsp;Greg Milburn ,&nbsp;Autumn Conger ,&nbsp;Paul Anaya ,&nbsp;Kenneth S. Campbell ,&nbsp;Alicia Lundby ,&nbsp;Kyoung Jae Won ,&nbsp;Cord Brakebusch","doi":"10.1016/j.mbplus.2022.100113","DOIUrl":"10.1016/j.mbplus.2022.100113","url":null,"abstract":"<div><p>Many heart diseases are associated with fibrosis, but it is unclear whether different types of heart disease correlate with different subtypes of activated fibroblasts and to which extent such diversity is modeled during <em>in vitro</em> activation of primary cardiac fibroblasts. Analyzing the expression of 82 fibrosis related genes in 65 heart failure (HF) patients, we identified a panel of 12 genes clearly distinguishing HF patients better from healthy controls than measurement of the collagen-related hydroxyproline content. A subcluster enriched in ischemic HF was recognized, but not for diabetes, high BMI, or gender. Single-cell transcriptomic analysis of <em>in vitro</em> activated mouse cardiac fibroblasts distinguished 6 subpopulations, including a contractile Acta2^high precursor population, which was predicted by time trajectory analysis to develop into Acta2^low subpopulations with high production of extracellular matrix molecules. The 12 gene profile identified in HF patients showed highest similarity to the fibroblast subset with the strongest expression of extracellular matrix molecules. Population markers identified were furthermore able to clearly cluster different disease stages in a murine model for myocardial infarct. These data suggest that major features of cardiac fibroblast activation in heart failure patients, in murine heart disease models<em>,</em> and in cell culture of primary murine cardiac fibroblast are shared.</p></div>","PeriodicalId":52317,"journal":{"name":"Matrix Biology Plus","volume":"15 ","pages":"Article 100113"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9253475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}