Abstract 19153: Resident Adult Rat Cardiac Stem Cells Fulfill Koch's Postulates as the Causative Agents for Myocardial Regeneration and Homeostasis
The role of endogenous adult c-kit positive (c-kitpos) cardiac stem cells (eCSCs) in patho-physiological cardiac remodelling has yet to be fully accepted. We tested the endogenous regenerative capacity of c-kitpos eCSCs after acute diffuse myocardial tissue damage by ISO in the adult rat (n=150), which kills 8–10% of myocytes and produces acute ventricular failure. The role of eCSCs in restoring myocytes and ventricular function was assessed by eliminating proliferating eCSCs and their cycling progeny with 5-flurouracil for 28 days after ISO (ISO+5-FU). This blocked eCSC expansion and new myocyte formation, causing a severe myocyte deficit compared to ISO alone, where regeneration was normally active. ISO+5-FU-treated animals did not recover ventricular function, developing overt cardiac failure. To ascertain a causal relationship between eCSCs and myocardial recovery, we replenished the myocardial eCSC population in ISO+5-FU-treated hearts and after recovery eliminated transplanted CSCs and their progeny. Clonogenic c-kitpos CSCs tagged with GFP (CSCGFP) or expressing Lac-Z and the herpes simplex virus thymidine kinase (TK) suicide gene (CSCβ-Gal/TK) were injected through the tail vein of ISO+5-FU treated rats. These cells homed to, nested and proliferated in ISO+5-FU damaged myocardium, restoring the normal complement of c-kitpos CSCs. Furthermore, ∼8% of all cardiomyocytes were GFP- or β-galpos and chimeric hearts had restored ventricular function. To eliminate transplanted CSCβ-Gal/TK and their progeny, ganciclovir was administered to 5-FU+ISO+CSCβ-Gal/TK-treated rats, which reversed all recovered cellular and functional parameters: myocardium was devoid of β-galpos CSCs and their myocyte progeny with re-appearance of overt cardiac failure. Importantly, CSCGFP isolated from chimeric hearts showed all features of normal eCSCs, being self-renewing, clonogenic and multipotent. These recovered CSCGFP maintained regenerative ability when transplanted into infarcted heart. In conclusion, c-kitpos eCSCs in adult myocardium fulfil all four Koch's postulates as the myocardial regenerative agents. These eCSCs are necessary and sufficient for cellular, anatomic and functional recovery after diffuse myocardial injury.
- © 2010 by American Heart Association, Inc.