Rejuvenation of human cardiac progenitor cells with pim-1 kinase

Sadia Mohsin, Mohsin Khan, Jonathan Nguyen, Monique Alkatib, Sailay Siddiqi, Nirmala Hariharan, Kathleen Wallach, Megan Monsanto, Natalie Gude, Walter Dembitsky, Mark A. Sussman

Research output: Contribution to journalArticle

81 Scopus citations

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. (Circ Res. 2013;113:1169-1179.).

Original languageEnglish (US)
Pages (from-to)1169-1179
Number of pages11
JournalCirculation Research
Volume113
Issue number10
DOIs
StatePublished - Oct 25 2013
Externally publishedYes

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Keywords

  • Aging
  • Cell cycle proteins
  • Heart failure
  • Telomere lengthening

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mohsin, S., Khan, M., Nguyen, J., Alkatib, M., Siddiqi, S., Hariharan, N., Wallach, K., Monsanto, M., Gude, N., Dembitsky, W., & Sussman, M. A. (2013). Rejuvenation of human cardiac progenitor cells with pim-1 kinase. Circulation Research, 113(10), 1169-1179. https://doi.org/10.1161/CIRCRESAHA.113.302302