CD248 enhances mechanotransduction in specific fibroblasts subset responsible for scar formation to aggravate fibrosis in kidney
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ABSTRACT:
PROVIDER: PRJNA1009020 | ENA |
REPOSITORIES: ENA
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Project description:gene expression profiling of fibrotic kidney of unilateral ureteral obstruction (UUO) mice with or wothout CD248 knockout. The purose of this study was to confirm the gene expression changes of Cd248-/- fibrotic kidney compared with wild ype.
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Project description:Post-injury remodeling is a complex process involving temporal specific cellular interactions in the injured tissue where the resident fibroblasts play multiple roles, including inflammation induction and tissue remodeling. To dissect the molecular basis of these interactions, we performed single-cell and spatial transcriptome analysis in human and mouse hearts after myocardial infarction. A subset of fibroblasts identified by unique high expression of CD248 was strongly correlated with collagen synthesis and remodeling, and genetic deletion of CD248 in fibroblast ameliorated cardiac fibrosis and dysfunction following ischemia/reperfusion, highlighting the functional importance of CD248 positive fibroblasts in post-injury pathological remodeling. CD248 stabilizes TGF-βR Ⅰ protein and activates ACKR3 expression in fibroblast, leading to enhanced T cell adhesion and retention. This CD248 mediated fibroblast-T cell interaction is required to sustain fibroblast activation and scar expansion in injured heart. Disruption of this interaction using monoclonal antibody or Chimeric antigen receptor T cell reduces T cell infiltration, ameliorates ischemia/reperfusion-induced cardiac fibrosis and improves heart function. Therefore, single cell and spatial molecular profiling in post-injury heart has uncovered a CD248 specific subclass of fibroblast with a critical role in fibroblast-T cell interaction and a new potential therapy to treat tissue fibrosis.
2025-01-24 | GSE287283 | GEO
Project description:Post-injury remodeling is a complex process involving temporal specific cellular interactions in the injured tissue where the resident fibroblasts play multiple roles, including inflammation induction and tissue remodeling. To dissect the molecular basis of these interactions, we performed single-cell and spatial transcriptome analysis in human and mouse hearts after myocardial infarction. A subset of fibroblasts identified by unique high expression of CD248 was strongly correlated with collagen synthesis and remodeling, and genetic deletion of CD248 in fibroblast ameliorated cardiac fibrosis and dysfunction following ischemia/reperfusion, highlighting the functional importance of CD248 positive fibroblasts in post-injury pathological remodeling. CD248 stabilizes TGF-βR Ⅰ protein and activates ACKR3 expression in fibroblast, leading to enhanced T cell adhesion and retention. This CD248 mediated fibroblast-T cell interaction is required to sustain fibroblast activation and scar expansion in injured heart. Disruption of this interaction using monoclonal antibody or Chimeric antigen receptor T cell reduces T cell infiltration, ameliorates ischemia/reperfusion-induced cardiac fibrosis and improves heart function. Therefore, single cell molecular profiling in post-injury heart has uncovered a CD248 specific subclass of fibroblast with a critical role in fibroblast-T cell interaction and a new potential therapy to treat tissue fibrosis.
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Project description:Male urethral stricture disease (USD) is characterized by scar formation, whose molecular mechanism is still lack. In this study, we performed comprehensive proteomic landscape of USD with 12 scar tissues and 5 matched normal adjacent tissues (NATs). Comparative analysis disclosed the ECM signaling and complement cascade were overrepresented in the scar tissues, in which COL11A1, CNN2, and CD248 would play positive impacts.
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Project description:The mammalian heart possesses a poor ability to regenerate after acute ischemic cardiac injury and lost cardiac muscle is replaced by scar tissue. Multiple clinical studies demonstrate that the size of scar tissue following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors that regulate the size of scar after ischemic cardiac injury. In this report, we demonstrate that collagen V, a fibrillar collagen and a minor constituent of heart scars regulates the size of heart scars after ischemic cardiac injury. Depletion of collagen V in heart scars in two independent animal models led to a significant and paradoxical increase in post infarction scar tissue size with worsening of heart function. A systems genetics approach analyzing genes versus traits across 100 in-bred strains of mice independently demonstrated that collagen V is a critical driver of post injury heart function. We show that collagen V deficiency alters the ultra-structure and mechanical properties of scar tissue that make it more vulnerable to expansion. There is altered reciprocal feedback between matrix and cells that induce expression of specific mechanosensitive integrins which drive fibroblast activation and increased ECM gene expression. Scar size increases. Administration of cilengitide, an inhibitor of specific integrins, completely rescues the phenotype of increased post injury scarring, myofibroblast formation and cardiac dysfunction in collagen V deficient mice. These observations demonstrate that collagen V, a structural constituent of heart scar tissue regulates scar size in an integrin dependent manner.
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Project description:The mammalian heart possesses a poor ability to regenerate after acute ischemic cardiac injury and lost cardiac muscle is replaced by scar tissue. Multiple clinical studies demonstrate that the size of scar tissue following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors that regulate the size of scar after ischemic cardiac injury. In this report, we demonstrate that collagen V, a fibrillar collagen and a minor constituent of heart scars regulates the size of heart scars after ischemic cardiac injury. Depletion of collagen V in heart scars in two independent animal models led to a significant and paradoxical increase in post infarction scar tissue size with worsening of heart function. A systems genetics approach analyzing genes versus traits across 100 in-bred strains of mice independently demonstrated that collagen V is a critical driver of post injury heart function. We show that collagen V deficiency alters the ultra-structure and mechanical properties of scar tissue that make it more vulnerable to expansion. There is altered reciprocal feedback between matrix and cells that induce expression of specific mechanosensitive integrins which drive fibroblast activation and increased ECM gene expression. Scar size increases. Administration of cilengitide, an inhibitor of specific integrins, completely rescues the phenotype of increased post injury scarring, myofibroblast formation and cardiac dysfunction in collagen V deficient mice. These observations demonstrate that collagen V, a structural constituent of heart scar tissue regulates scar size in an integrin dependent manner.
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Project description:3mm punch biopsies were taken from a healed normotrophic scar and a contralateral matched control site in burn patients with a scar at least 1 year old. Fibroblasts were cultured from explants to passage 2 and RNA was extracted and run on expression arrays to examine differences in scar and control fibroblast gene expression Normotrophic scar maintains its abnormal scar phenotype for the rest of the patients life, long after the injury has healed. Differences in gene expression may reaveal target genes that can be modulated to improve scar appearance
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