Strategy For Cardiac Repair Research Articles

Regenerating the heart

Cell-based cardiac repair offers the promise of rebuilding the injured heart from its component parts. Work began with committed cells such as skeletal myoblasts, but recently the field has expanded to explore an array of cell types, including bone marrow cells, endothelial progenitors, mesenchymal stem cells, resident cardiac stem cells, and both mouse and human embryonic stem cells. A related strategy for cardiac repair involves cell mobilization with factors such as cytokines. Translation of cell-based approaches to the clinic has progressed rapidly, and clinical trials using autologous skeletal myoblasts and bone marrow cells are under way. Many challenges remain before the vision of healing an infarct by muscle regeneration can be realized. Future research is likely to focus on improving our ability to guide the differentiation of stem cells, control their survival and proliferation, identify factors that mediate their homing and modulate the heart's innate inflammatory and fibrotic responses.

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.

Transmural Replacement of Myocardium after Skeletal Myoblast Grafting into the Heart: Too Much of a Good Thing?

Skeletal myoblasts form stable grafts in the heart and may improve myocardial performance after infarction. The current study compared the ability of different immortalized myoblast lines, or primary myoblast isolates, to form grafts in the normal or cryoinjured heart. With a constant dose of 6 × 10 6 cells, primary rat myoblasts and mouse C2C12 myoblasts formed similarly large skeletal muscle grafts in recipient rat hearts. Grafts often caused transmural replacement of the myocardium in normal hearts and almost completely replaced the damaged region in cryoinjured hearts. To test for possible artifacts due to immunosuppression and xenografting (mouse C2C12 cells into rat hearts), we grafted 1 × 10 6 mouse MM14 or C2C12 myoblasts into normal hearts of nude mice. Again, the C2C12 grafts caused transmural replacement of the left ventricular wall and distorted the epi- and endocardial contours. The MM14 cells, however, formed relatively small grafts. The C2C12 grafts showed substantially higher BrdU incorporation rates at day 4 compared with MM14 cells, suggesting that ongoing proliferation was responsible for the increased graft size. None of the three skeletal muscle cell types expressed detectable amounts of the gap junction protein connexin43 after grafting. The intercellular adhesion protein N-cadherin was not expressed in primary skeletal muscle grafts, but was spotty or abundant in C2C12- and MM14-derived grafts, respectively. The absence of connexin43 precluded electrical coupling between graft and host muscle cells. Thus, when sufficient amounts of proliferation occur after grafting, skeletal muscle cells can effectively replace the volume of lost myocardium. Excess proliferation, however, can cause grafts to expand the ventricular wall and possibly impair pump function. Optimal cardiac repair strategies may need to incorporate methods to control graft cell proliferation.