Pre-existing fibroblasts of epicardial origin are the primary source of pathological fibrosis in cardiac ischemia and aging
| Autor: | Eric M. Small, Ronald A. Dirkx, Lissette S. Velasquez, Adwiteeya Misra, Deanne Mickelsen, Ryan M. Burke, Pearl Quijada, Janet K. Lighthouse |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cardiac function curve medicine.medical_specialty Aging Serum Response Factor Cardiac fibrosis Population Diastole Myocardial Ischemia 030204 cardiovascular system & hematology Article 03 medical and health sciences 0302 clinical medicine Fibrosis Internal medicine Serum response factor Medicine Animals Cell Lineage Progenitor cell education WT1 Proteins Molecular Biology Mice Knockout education.field_of_study Heart development Ventricular Remodeling business.industry Stem Cells Heart Fibroblasts medicine.disease 030104 developmental biology Cardiology cardiovascular system Trans-Activators Cardiology and Cardiovascular Medicine business Pericardium |
| Zdroj: | Journal of molecular and cellular cardiology. 129 |
| ISSN: | 1095-8584 |
| Popis: | 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 Mrtfs 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect