Mending broken hearts

Rat mesenchymal stem cells modified to express Akt show potential for the regeneration of the heart

Aug 11, 2003
David Secko(dmsecko@interchange.ubc.ca)

Human cardiac disease involving a disruption of blood flow, for example, in myocardial infarction, initiates a process in which heart muscle cells (the myocardium) die. Natural repair mechanisms do exist, including an enlargement of the heart, an increase in the number of cells present, and the traveling of bone-marrow–derived stem cells (BMCs) to effect some repair, but none are effective in the long term. To effect additional repair, harvesting and direct injection of BMCs and mesenchymal stems cells (MSCs) into ischemic myocardium has been undertaken. This has met with partial success and is partly explained by the poor viability of the transplanted cells. In the August 10 Nature Medicine, Abeel A. Mangi and colleagues at Brigham and Women's Hospital and Harvard Medical School genetically engineered MSCs designed to overcome previous problems with cell death during transplantation into infarcted hearts (Nature Medicine, DOI:10.1038/nm912, August 10, 2003).

Mangi et al. grew large quantities of adult rat MSCs in mixed culture with hematopoietic cells and purified the MSCs > 99.9% using preferential attachment to polystyrene surfaces and negative paramagnetic bead sorting. The purified MSCs were then genetically modified with the use of retroviruses to express a murine version of the cell survival protein Akt in order that the cells would not undergo apoptosis upon transplantation into infracted hearts. They observed that Akt-expressing MSCs showed an 80% reduction in apoptosis in vitro after 24 hours of hypoxia and also observed this effect in vivo through the injection of 5 x 106 Akt MSCs into myocardial infarcted female rats. The injected MSCs developed into cardiac myocyte-like cells in a manner restricted to injured myocardium, since it was not observed in uninjured tissue. This injection was also associated with regeneration of lost myocardial volume, normalized cardiac function, and the prevention of pathological remodeling, all pointing to improved cardiac function resulting from the Akt MSCs.

"We speculate that future therapy for acute myocardial infarction may involve transplantation of MSCs overexpressing Akt to facilitate the repair of the damaged heart," conclude the authors. The genetic engineering of stem cells, perhaps encompassing a combination of gene and cell therapy, may hold great potential for effective treatments involving regenerative medicine.