Rejuvenation of Human Cardiac Progenitor Cells With Pim-1 Kinase

Abstract

Rationale Myocardial function is enhanced by adoptive transfer of human cardiac progenitor cells (hCPCs) into a pathologically challenged heart. However, advanced age, comorbidities, and myocardial injury in patients with heart failure constrain the proliferation, survival, and regenerative capacity of hCPCs. Rejuvenation of senescent hCPCs will improve the outcome of regenerative therapy for a substantial patient population possessing functionally impaired stem cells. Objective Reverse phenotypic and functional senescence of hCPCs by ex vivo modification with Pim-1. Methods and Results C-kit–positive hCPCs were isolated from heart biopsy samples of patients undergoing left ventricular assist device implantation. Growth kinetics, telomere lengths, and expression of cell cycle regulators showed significant variation between hCPC isolated from multiple patients. Telomere length was significantly decreased in hCPC with slow-growth kinetics concomitant with decreased proliferation and upregulation of senescent markers compared with hCPC with fast-growth kinetics. Desirable youthful characteristics were conferred on hCPCs by genetic modification using Pim-1 kinase, including increases in proliferation, telomere length, survival, and decreased expression of senescence markers. Conclusions Senescence characteristics of hCPCs are ameliorated by Pim-1 kinase resulting in rejuvenation of phenotypic and functional properties. hCPCs show improved cellular properties resulting from Pim-1 modification, but benefits were more pronounced in hCPC with slow-growth kinetics relative to hCPC with fast-growth kinetics. With the majority of patients with heart failure presenting advanced age, infirmity, and impaired regenerative capacity, the use of Pim-1 modification should be incorporated into cell-based therapeutic approaches to broaden inclusion criteria and address limitations associated with the senescent phenotype of aged hCPC.

Nuclear Calcium/Calmodulin-dependent Protein Kinase II Signaling Enhances Cardiac Progenitor Cell Survival and Cardiac Lineage Commitment

“…Proliferation-Overexpression of CaMKII␦B in CPCs presented phenotypic characteristics that are relevant to increased cardiomyogenic differentiation (35). In support of this, CPCe␦B show decreased proliferative potential (Fig.…”

Recent Developments in Cardiovascular Stem Cells

“…[103][104][105][106][107] Genetic modification of aged human CPCs with Pim-1 kinase results in remarkable rejuvenation of the CPCs associated with enhanced proliferation, increased telomere lengths, and decreased susceptibility to replicative senescence. 104,105 Likewise, activation of NOTCH1 signaling pathway is implicated in rejuvenation of myogenic responses to satellite muscle cells. 108 Activation of telomere-telomerase axis is known to contribute to cell survival and proliferation, and to prevent cellular senescence.…”

Insights Into Signaling in Cell-Based Therapy for Heart Disease

“…77 Cardiac stem cells engineered to overexpress Pim-1 have increased survival, proliferation, and ability to regenerate and repair damaged myocardium. 74,78 Proliferation Proliferation is a vital component of stem cell efficacy both because stem cells must be expanded in vitro prior to administration and because proliferation after transplantation increases the graft population. Several growth factors have been used to increase MSC proliferation in vitro.…”