Pathogenic potential of Hic1 expressing cardiac stromal progenitors
The cardiac stroma contains multipotent mesenchymal progenitors. However, lineage relationships within cardiac stromal cells are still poorly understood. Here, we identify heart-resident 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). HighlightsO_LIA subpopulation of PDGFRa+, Sca-1+ cells, previously considered to be a sub-type of cardiac fibroblasts, are multipotent mesenchymal progenitors, C_LIO_LICardiac damage triggers the differentiation of PDGFRa+ Sca-1+ cells into Sca-1- cells expressing a fibrogenic transcriptional programme, C_LIO_LIBlockade of the cFAP-to-fibroblast transition by Nilotinib ameliorated cardiac dysfunction post-MI and modulated cardiac remodelling. C_LIO_LIStudies performed on a model of experimentally-induced AC confirmed that cFAPs are a source of both cardiac fibroblasts and adipocytes in vivo. C_LIO_LIConversely, 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 mesenchymal progenitors that contribute to different forms of cardiac degeneration depending on the damage setting. C_LI