Abstract 1917: Dual Role of the IGF System in the Modulation of the Akt-mTOR Pathway in Human Cardiac Progenitor Cells
We have identified that human cardiac progenitor cells (hCPCs) express IGF-1 receptors (IGF-1R) which can be activated by both IGF-1 and IGF-2 ligands. However, IGF-1 promotes hCPC proliferation while IGF-2 favors hCPC commitment and the acquisition of the cardiomyocyte phenotype. The objective of the current study was to determine whether the differential response of hCPCs to these growth factors was dictated by distinct downstream effector pathways. For this purpose, the Akt-mTOR signaling mechanism was analyzed in IGF-1R-positive hCPCs exposed in vitro to IGF-1 or IGF-2 for 10, 15 and 30 minutes. With both ligands, IGF-1R underwent a similar degree of autophosphorylation at the three tyrosine residues located in the kinase domain of the receptor. Although total Akt did not differ in hCPCs stimulated with IGF-1 and IGF-2, phosphorylation of Akt at Thr308 and Ser473 showed a distinct temporal pattern of expression. IGF-2 led to a transient increase in the levels of phospho-Akt which were high at 10 –15 minutes but were significantly decreased at 30 minutes. In contrast, IGF-1 resulted in a stable upregulation of phospho-Akt that persisted up to 30 minutes. Phosphorylation of mTOR at Ser2448 was higher in the presence of IGF-1 pointing to a greater ability of mTOR to interact with Rictor and Raptor. Consistently, the mTOR-Rictor complex, TORC1, was more abundant in IGF-1 than in IGF-2 treated hCPCs. However, the upregulation of Raptor was more pronounced in hCPCs exposed to IGF-2. Collectively, these data indicate that IGF-1 leads to a persistent activation of Akt that may be critical for hCPC replication and survival while IGF-2 may act preferentially on TORC2 which can condition the autocrine release of IGF-2. This process may attenuate IGF-1 function, interfering with cell proliferation and facilitating cell differentiation. In conclusion, the separate function of IGF-1 and IGF-2 on hCPCs may have important implications in the implementation of cell therapy for the failing human heart: autologous hCPCs activated by IGF-1 can be employed to rapidly expand the pool of functionally competent progenitor cells while IGF-2 could be introduced subsequently to enhance myocyte formation and their acquisition of the adult cell phenotype.