Abstract 13837: Fibronectin is Essential for Cardiac Stem Cell Response Following Myocardial Infarction
Background: Cardiac Progenitor Cells (CPCs) show promise in early clinical trials for treatment of heart failure despite limited mechanistic knowledge of the endogenous regenerative response following myocardial infarction (MI). Fibronectin (Fn), an extracellular matrix protein, is highly expressed early during development, decreases with aging and re-appears after pathological injury such as MI. Fn is a component of the cardiac stem cell niche in the adult heart so we sought to determine the role of Fn upon the endogenous CPC response after MI.
Methods: Since germline genetic deletion of Fn leads to cardiovascular malformation and embryonic lethality, tamoxifen sensitive conditional Fn knock-down (Fn-KD) animals were created. At 12 weeks of age mice were subjected to MI with follow-up monitoring of cardiac function by echocardiography. DNA synthesis indicative of cell replication was tracked by administration of BrdU for ten days following MI to track committed CPC progeny. Heart specimens were assessed using immunohistochemistry, immunoblot and qRT-PCR at 7 days and 12 weeks post challenge, with the impact of Fn deletion upon CPC biology determined by cell death and proliferation assays in vitro.
Results: CPC expansion showed a close correlation with Fn expression in wild type animals during physiological development and after MI. Furthermore, CPCs localized to regions of high Fn expression in the heart. Fn induced protection and proliferation of CPCs via β1-FAK-Pim1 cascade in vitro. CPC expansion was reduced by 43% at 7 days post MI in Fn-KD animals compared to controls and the percentage of CPCs positive for the proliferation marker Ki67 was also reduced by 39.7%. Cardiac function in control and Fn-KD mice remained equivalent up to 2 weeks post MI, however, by 4 weeks function started to decline in Fn-KD whereas control animals were stable. Ejection fraction was 16.4 +/-1.5% in KD animals compared to 26.6 +/-1.8% in controls at 12 weeks post MI. Commitment of CPCs, which were labeled with BrdU early after MI, is currently under investigation.
Conclusion: These results indicate previously unidentified cardioprotective and pro-reparative roles for FN upon endogenous CPC response after MI opening up novel treatment option to improve cardiac regeneration.
- Stem/progenitor cells
- Progenitor cell
- Regenerative medicine stem cells
- Cardiac regeneration
- Extracellular matrix
- © 2012 by American Heart Association, Inc.