Pathogenic potential of Hic1 expressing cardiac stromal progenitors

• DOI: 10.1101/544403
• Publication Date: 2019-02-08T21:31:58Z
• Authors: H Soliman; B Paylor; W Scott; DR Lemos; CK Chang; M Arostegui; M Low; C Lee; D Fiore; P Braghetta; V Pospichalova; CE Barkauskas; V Korinek; A Rampazzo; K MacLeod; TM Underhill; FM Rossi
• Keywords: PDGFRA; Cardiac Fibrosis

Abstract The cardiac stroma contains multipotent mesenchymal progenitors. However, lineage relationships within stromal cells are still poorly understood. Here, we identify heart-resident PDGFRa + Sca-1 as 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 leads improvements in heart function. In the undamaged heart, activation cFAPs through lineage-specific deletion quiescence factor Hic1 reveals additional pathogenic potential, causing fibro-fatty infiltration myocardium driving major pathological features Arrhythmogenic Cardiomyopathy (AC). Highlights A subpopulation , cells, previously considered be a sub-type fibroblasts, progenitors, Cardiac triggers into - expressing transcriptional programme, Blockade cFAP-to-fibroblast transition Nilotinib ameliorated dysfunction post-MI modulated remodelling. Studies performed on model experimentally-induced AC confirmed source both fibroblasts adipocytes vivo . Conversely, means transcription Hic1, resulted fibro/fatty degeneration alterations reminiscent AC. Collectively, our findings proportion what commonly termed “fibroblasts” actually progenitors contribute different forms depending setting.