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


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.
Fischer
Kimberlee M
KM
San Diego State Heart Institute, San Diego State University, San Diego, CA, USA.
Cottage
Christopher T
CT
Wu
Weitao
W
Din
Shabana
S
Gude
Natalie A
NA
Avitabile
Daniele
D
Quijada
Pearl
P
Collins
Brett L
BL
Fransioli
Jenna
J
Sussman
Mark A
MA
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005818:Genetic Engineering; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*
D019009:Proto-Oncogene Proteins c-kit; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1