Cell and gene therapy for severe heart failure patients: the time and place for Pim-1 kinase

Abstract

Regenerative therapy in severe heart failure patients presents a challenging set of circumstances including a damaged myocardial environment that accelerates senescence in myocytes and cardiac progenitor cells. Failing myocardium suffers from deterioration of contractile function coupled with impaired regenerative potential that drives the heart toward decompensation. Efficacious regenerative cell therapy for severe heart failure requires disruption of this vicious circle that can be accomplished by alteration of the compromised myocyte phenotype and rejuvenation of progenitor cells. This review focuses upon potential for Pim-1 kinase to mitigate chronic heart failure by improving myocyte quality through preservation of mitochondrial integrity, prevention of hypertrophy and inhibition of apoptosis. In addition, cardiac progenitors engineered with Pim-1 possess enhanced regenerative potential, making Pim-1 an important player in future treatment of severe heart failure.

Figure 1. Application of Pim-1 genetic engineering for cardiac progenitor cells, cardiomyocytes, and the pathologically damaged myocardium of severe heart failure

(A) 1. Myocytes suffering from replicative senescence, exposure to the senescent “secretome”, with shortened telomeres and impaired mitochondrial function exhibit reduced contractile function. 2. Myocytes “rejuvenated” by Pim-1 overexpression possess heightened survival and metabolic activity together with increased contractile function. 3. CPCs with compromised proliferative capability, short telomeres as a result of replicative and premature senescence, exhibiting compromised regenerative potential. 4. CPCs engineered with Pim-1 recover proliferative potential, higher metabolic activity and elongated telomeres, thereby having an increased regenerative potential. (B) Conceptual representation of Pim-1 mediated molecular interventional strategy to treat severe heart failure. Decompensated heart suffering from replicative and premature senescence with aged/damaged myocytes and senescent stem cells (top). Time and place for Pim-1 gene therapy intervention is indicated by the arrow (upper panel). Pim-1 mediated priming of the environment results in improved myocyte quality with subsequent beneficial paracrine effect on the endogenous CPCs (middle of panel). Delivery of Pim-1 “rejuvenated” CPCs into a modified environment is indicated by the arrow (middle panel). Injection of Pim-1 engineered CPCs results in myocardial regeneration and improved contractile function (lower panel) in mouse CPCs, human CPCs in mouse and human CPCs in swine (Fischer et al., Mohsin et al., Karantalis et al.). CPCs: Cardiac progenitor cell