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 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). 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-1- cells 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 mesenchymal progenitors that contribute to different forms of cardiac degeneration depending on the damage setting.