Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts

Nat Med. 2003 Sep;9(9):1195-201. doi: 10.1038/nm912. Epub 2003 Aug 10.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Biomarkers / analysis
  • Cells, Cultured
  • Collagen / metabolism
  • Hematopoietic Stem Cells / physiology
  • In Vitro Techniques
  • Injections
  • Male
  • Mesoderm / cytology*
  • Mesoderm / physiology
  • Mice
  • Myocardial Infarction / pathology
  • Myocardial Infarction / therapy
  • Myocardial Ischemia / pathology*
  • Myocardial Ischemia / therapy*
  • Myocytes, Cardiac / pathology
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Retroviridae / genetics
  • Stem Cell Transplantation / methods*
  • Transduction, Genetic
  • beta-Galactosidase / genetics

Substances

  • Biomarkers
  • Proto-Oncogene Proteins
  • Collagen
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • beta-Galactosidase