Although bone marrow-derived mesenchymal stem cells (MSCs) have been shown to develop into cardiac muscle in vivo, their potential as a treatment for cardiac disease is limited, in part, by their poor viability after transplantation.

Victor Dzau and colleagues proposed that by engineering MSCs to overexpress Akt — a serine threonine kinase that is necessary for cell survival — they would be more resistant to cell death and so enhance cardiac repair when transplanted into an ischaemic rat heart.

To genetically modify purified rat MSCs, the authors transduced them with retrovirus that carried the mouse Akt1 cDNA in a stem-cell virus vector. The significant increase in the total Akt signal showed that Akt1 was successfully incorporated and expressed. Akt activity in these transgenic MCSs (Akt-MSCs) was greater than in controls, and the activity increased further in response to hypoxia. This increased activity coincided with an 80% decrease in the apoptosis of Akt-MCSs in vitro and in vivo.

Next, Dzau and co-workers injected Akt-MSCs into the heart of adult female rats, 60 minutes after heart attack. Not only did they find that the MSCs migrated to the injured site and developed into cardiac myocyte-like cells that formed connections with existing cardiac myocytes, but also the volume of the affected area in these rats was dramatically reduced, the cardiac function was normalized and cardiac remodelling was prevented. Interestingly, these cellular responses were not seen when Akt-MCSs were transplanted into uninjured normal myocardium, and, encouragingly, the authors were only able to induce the Akt-MSCs to develop into cardiac myocyte-like cells.

Questions still remain about the mechanism by which MSCs develop into cardiac myocyte-like cells — by fusion with existing native cells or by differentiation — and research is needed to define exactly how MSCs exert their therapeutic effect. Nonetheless, the authors believe that this approach is the way forward for cardiac repair and regeneration: “This novel, cell-based, gene-therapy approach has the potential ... to make cell-based therapy an effective treatment for human cardiac disease”.