Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts.
Transplantation of adult bone marrow-derived mesenchymal stem cells has been proposed as a strategy for cardiac repair following myocardial damage. However, poor cell viability associated with transplantation has limited the reparative capacity of these cells in vivo. In this study, we genetically engineered rat mesenchymal stem cells using ex vivo retroviral transduction to overexpress the prosurvival gene Akt1 (encoding the Akt protein). Transplantation of 5 x 10(6) cells overexpressing Akt into the ischemic rat myocardium inhibited the process of cardiac remodeling by reducing intramyocardial inflammation, collagen deposition and cardiac myocyte hypertrophy, regenerated 80-90% of lost myocardial volume, and completely normalized systolic and diastolic cardiac function. These observed effects were dose (cell number) dependent. Mesenchymal stem cells transduced with Akt1 restored fourfold greater myocardial volume than equal numbers of cells transduced with the reporter gene lacZ. Thus, mesenchymal stem cells genetically enhanced with Akt1 can repair infarcted myocardium, prevent remodeling and nearly normalize cardiac performance.
Mangi
Abeel A
AA
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts, 02115 USA.
Noiseux
Nicolas
N
Kong
Deling
D
He
Huamei
H
Rezvani
Mojgan
M
Ingwall
Joanne S
JS
Dzau
Victor J
VJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000032:analysis; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000502:physiology; D066298:In Vitro Techniques; D007267:Injections; D008297:Male; D008648:Mesoderm / Q000166:cytology* / Q000502:physiology; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000473:pathology* / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D033581:Stem Cell Transplantation / Q000379:methods*; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000235:genetics
D015415:Biomarkers; D011518:Proto-Oncogene Proteins; D003094:Collagen; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D001616:beta-Galactosidase