Pathogenic Potential of Hic1-Expressing Cardiac Stromal Progenitors

Abstract

The cardiac stroma contains multipotent mesenchymal progenitors. However, lineage relationships within cardiac stromal cells are still poorly understood. Here, we identify heartresident PDGFRa + Sca-1 + cells as cardiac Fibro/Adipogenic Progenitors (cFAPs) and show that they respond to ischemic damage by generating fibrogenic cells. Pharmacological blockade of this differentiation step with an anti-fibrotic tyrosine kinase inhibitor decreases post-myocardial infarction (MI) remodeling and leads to improvements in heart function. In the undamaged heart, activation of cFAPs through lineage-specific deletion of the quiescence factor Hic1 reveals additional pathogenic potential, causing fibro-fatty infiltration of the myocardium and driving major pathological features of Arrhythmogenic Cardiomyopathy (AC). Highlights• A subpopulation of PDGFRa + , Sca-1 + cells, previously considered to be a sub-type of cardiac fibroblasts, are multipotent mesenchymal progenitors,• Cardiac damage triggers the differentiation of PDGFRa + Sca-1 + cells into Sca-1cells expressing a fibrogenic transcriptional programme,• Blockade of the cFAP-to-fibroblast transition by Nilotinib ameliorated cardiac dysfunction post-MI and modulated cardiac remodelling.• Studies performed on a model of experimentally-induced AC confirmed that cFAPs are a source of both cardiac fibroblasts and adipocytes in vivo.• Conversely, in the undamaged heart, activation of cFAPs by means of lineage-specific deletion of transcription factor Hic1, resulted in fibro/fatty cardiac degeneration and pathological alterations reminiscent of AC. Collectively, our findings show that a proportion of what are commonly termed "fibroblasts" are actually multipotent .

Human skeletal muscle CD90+fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients

“…As such, although inactive in vivo, the FAP CD90+ have an increased propensity to enter the cell cycle, which is associated with a larger cell size. This finding suggests that FAP CD90+ could be a subset of progenitor cells within FAPs that is poised for entry into cell cycle and further fibrogenic activation, as proposed for cardiac FAPs 53 . To examine this further, we decided to perform the limiting dilution and single-cell clonal assay.…”

Mesenchymal Stem Cells Adaptively Respond to Environmental Cues Thereby Improving Granulation Tissue Formation and Wound Healing

“…Two very recent studies have identified a subpopulation of perivascular MSCs in the heart and muscle, which are characterized by the expression of PDGFRα, stem cell antigen-1 (Sca-1, Ly6A) and the tumor repressor hypermethylated in cancer 1 (Hic1) (Scott et al, 2019;Soliman et al, 2020). Both studies have shown that Hic1 + MSCs play important roles in the homeostasis and repair of heart and skeletal muscle, differentiate into different cell types including fibroblasts and are kept in a resting state by Hic1 (Kim and Braun, 2020).…”

“…Both studies have shown that Hic1 + MSCs play important roles in the homeostasis and repair of heart and skeletal muscle, differentiate into different cell types including fibroblasts and are kept in a resting state by Hic1 (Kim and Braun, 2020). The transcription repressor Hic1 is required for maintaining quiescence, since deletion of Hic1 leads to activation and expansion of MSCs, and subsequently leads to pathological fibrosis of heart (Soliman et al, 2020) and skeleton muscle (Scott et al, 2019), respectively. The exact molecular targets of Hic1 remain elusive.…”

“…Their relationship to En1 lineage positive fibroblasts or Dlk-1 positive fibroblasts is currently unresolved. Employing single cell sequencing analysis combined with in vivo tracing analysis and genetic deletion of quiescence or other markers have recently allowed to better define the origin and the lineage hierarchy of mesenchymal progenitors and stem cells in tissue and organ regeneration (Scott et al, 2019;Soliman et al, 2020).…”

Human Cell Modeling for Cardiovascular Diseases

“…In order to investigate a role of FAPs in ACM, researchers verified the expression of desmosome proteins, found only in adipogenic but not in fibrogenic subpopulations [35]. Experiments on mice revealed that the inhibition of FAPs fibrogenic differentiation could be a therapeutic strategy after myocardial infarction, but further studies on human models are necessary [36].…”