Pre-existing fibroblasts of epicardial origin are the primary source of pathological fibrosis in cardiac ischemia and aging. (April 2019)

• Record Type: Journal Article
• Authors: Quijada, Pearl; Misra, Adwiteeya; Velasquez, Lissette S.; Burke, Ryan M.; Lighthouse, Janet K.; Mickelsen, Deanne M.; Dirkx, Ronald A.; Small, Eric M.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 129(2019)
• Page Start: 92
• Page End: 104
• Publication Date: 2019-04
• Subjects: Epicardium -- Fibrosis -- Myocardial infarction -- Aging -- Genetic lineage tracing; MRTF myocardin-related transcription factors -- SRF serum-response factor -- WT1 Wilms Tumor 1 -- EPDC epicardium-derived progenitor cell -- PDGFRα platelet-derived growth factor – alpha; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2019.01.015
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Serum response factor (SRF) and the SRF co-activators myocardin-related transcription factors (MRTFs) are essential for epicardium-derived progenitor cell (EPDC)-mobilization during heart development; however, the impact of developmental EPDC deficiencies on adult cardiac physiology has not been evaluated. Here, we utilize the Wilms Tumor-1 ( Wt1 )-Cre to delete Mrtf s or Srf in the epicardium, which reduced the number of EPDCs in the adult cardiac interstitium. Deficiencies in Wt1 -lineage EPDCs prevented the development of cardiac fibrosis and diastolic dysfunction in aged mice. Mice lacking MRTF or SRF in EPDCs also displayed preservation of cardiac function following myocardial infarction partially due to the depletion of Wt1 lineage-derived cells in the infarct. Interestingly, depletion of Wt1 -lineage EPDCs allows for the population of the infarct with a Wt1 -negative cell lineage with a reduced fibrotic profile. Taken together, our study conclusively demonstrates the contribution of EPDCs to both ischemic cardiac remodeling and the development of diastolic dysfunction in old age, and reveals the existence of an alternative Wt1 -negative source of resident fibroblasts that can populate the infarct.