Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation.
We previously reported that intramyocardial injection of bone marrow-derived mesenchymal stem cells overexpressing Akt (MSC-Akt) efficiently repaired infarcted rat myocardium and improved cardiac function. Controversy still exists over the mechanisms by which MSC contribute to tissue repair. Herein, we tested if cellular fusion of MSC plays a determinant role in cardiac repair. We injected MSC expressing Cre recombinase, with or without Akt, into Cre reporter mice. In these mice, LacZ is expressed only after Cre-mediated excision of a loxP-flanked stop signal and is indicative of fusion. MSC engraftment within infarcted myocardium was transient but significantly enhanced by Akt. MSC fusion with cardiomyocytes was observed as early as 3 days, but was infrequent, and we found a low rate of differentiation of MSC into cardiomyocytes. MSC-Akt decreased infarct size at 3 days and restored early cardiac function. In conclusion, MSC-Akt improved early repair despite transient engraftment, low levels of cellular fusion, and differentiation. These new observations further confirm our recently reported data that early paracrine mechanisms mediated by MSC are responsible for enhancing the survival of existing myocytes and that Akt could alter the secretion of various cytokines and growth factors.
Noiseux
Nicolas
N
Department of Medicine, Brigham and Women's Hospital, Harvard University, Boston, MA 02115, USA.
Gnecchi
Massimiliano
M
Lopez-Ilasaca
Marco
M
Zhang
Lunan
L
Solomon
Scott D
SD
Deb
Arjun
A
Dzau
Victor J
VJ
Pratt
Richard E
RE
D000818:Animals; D002454:Cell Differentiation; D002459:Cell Fusion; D002478:Cells, Cultured; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism / Q000628:therapy*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014162:Transfection
D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D051057:Proto-Oncogene Proteins c-akt; C045073:Cre recombinase; D019426:Integrases