Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing pim-1 kinase

Kimberlee M. Fischer, Christopher T. Cottage, Weitao Wu, Shabana Din, Natalie A. Gude, Daniele Avitabile, Pearl Quijada, Brett L. Collins, Jenna Fransioli, Mark A. Sussman

Research output: Contribution to journalArticlepeer-review

Abstract

Background-: Despite numerous studies demonstrating the efficacy of cellular adoptive transfer for therapeutic myocardial regeneration, problems remain for donated cells with regard to survival, persistence, engraftment, and long-term benefits. This study redresses these concerns by enhancing the regenerative potential of adoptively transferred cardiac progenitor cells (CPCs) via genetic engineering to overexpress Pim-1, a cardioprotective kinase that enhances cell survival and proliferation. Methods and Results-: Intramyocardial injections of CPCs overexpressing Pim-1 were given to infarcted female mice. Animals were monitored over 4, 12, and 32 weeks to assess cardiac function and engraftment of Pim-1 CPCs with echocardiography, in vivo hemodynamics, and confocal imagery. CPCs overexpressing Pim-1 showed increased proliferation and expression of markers consistent with cardiogenic lineage commitment after dexamethasone exposure in vitro. Animals that received CPCs overexpressing Pim-1 also produced greater levels of cellular engraftment, persistence, and functional improvement relative to control CPCs up to 32 weeks after delivery. Salutary effects include reduction of infarct size, greater number of c-kit cells, and increased vasculature in the damaged region. Conclusions-: Myocardial repair is significantly enhanced by genetic engineering of CPCs with Pim-1 kinase. Ex vivo gene delivery to enhance cellular survival, proliferation, and regeneration may overcome current limitations of stem cell-based therapeutic approaches.

Original languageEnglish
Pages (from-to)2077-2087
Number of pages11
JournalCirculation
Volume120
Issue number21
DOIs
Publication statusPublished - Nov 2009

Keywords

  • Echocardiography
  • Gene therapy
  • Hemodynamics
  • Infarction

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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