Abstract 1542: Myocardial Damage Induces A Growth Factor Para/Autocrine Loop in the Spared Myocytes Which Fosters Cardiac Stem Cell Activation and Ensuing Myocyte Regeneration
Myocardial damage results in the increased expression of many growth factors and cytokines (GFs). c-kitpos cardiac stem cells (CSCs) are rapidly activated in response to myocardial injury and can mediate a vigorous myocyte regeneration response. However, the exact GF signaling pathway modulating CSC activation is largely unknown. We sought to investigate the response of the myocardium, with respect to GF expression and CSC activation, following diffuse myocardial injury. Isoproterenol (ISO; 5mgkg−1), injected as a single dose to male Wistar rats produced severe myocyte death (~8%) and myocyte hypertrophy, followed by an ~8-fold increase in CSCs as analyzed by FACS and immunohistochemistry. Real-time RT-PCR of RNA from isolated CSCs documented a rapid induction of cell cycle related genes followed by a progressive increase of transcripts for GATA4 and Nkx2.5 from day 1 to day 3. Also there was increased transcription of contractile genes (β-MHC, cardiac actin and cTnI) in differentiating CSCs at 3 days after ISO injury. These results were confirmed by immunohistochemistry. Subsequent new myocyte formation (BrdUpos/Ki67pos/p107pos) was significantly evident at 6 days and had reached ~5% by 28 days after ISO. Gene array analysis from purified myocyte populations identified IGF-1, HGF, SDF, TGF1β and Wnt-5 as rapidly and specifically up-regulated GFs immediately following injury. Accordingly, these factors were secreted into the extracellular space. These locally secreted GFs activate the corresponding receptors on the surface of CSCs promoting their downstream signaling, as demonstrated by Akt phosphorylation and/or nuclear translocation of β-catenin. In addition, the CSCs respond by inducing expression of the corresponding factors. This signaling cascade is responsible for the proliferation and consequent differentiation of the stem/precursor cells which results in the regeneration of myocytes. This auto/paracrine loop maintains the activated state of the CSCs for some time after the disappearance of the primary stimulus, supporting their growth and differentiation. Thus, to maintain cardiac homeostasis the CSCs depend on and respond to GFs produced by the surrounding myocytes, while myocyte maintenance depends on the progeny of the CSCs.