Rejuvenation of Human Cardiac Progenitor Cells with Pim-1 Kinase
Rationale: Myocardial function is enhanced by adoptive transfer of human cardiac progenitor cells (hCPC) into a pathologically challenged heart. However, advanced age, comorbidities, and myocardial injury in heart failure patients 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 (LVAD) 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 (hCPC-S) concomitant with decreased proliferation and upregulation of senescent markers compared to hCPC with fast growth kinetics (hCPC-F). 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. hCPC show improved cellular properties resulting from Pim-1 modification, but benefits were more pronounced in hCPC-S relative to hCPC-F. With the majority of heart failure patients presenting advanced age, infirmity, and impaired regenerative capacity, 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.
- Received July 30, 2013.
- Revision received September 13, 2013.
- Accepted September 16, 2013.