Enhancing Retention of Mesenchymal Stem Cells with Pro-survival Factors Promotes Angiogenesis in a Mouse Model of Limb Ischemia.

Mesenchymal stem/stromal cells (MSCs) offer great promise in the treatment of ischemic injuries including stroke, heart infarction and limb ischemia. However, poor cell survival after transplantation remains a major obstacle to achieve effective MSC therapies. To improve cell survival and retention, we transplanted human bone marrow MSCs with or without a specific pro-survival factor (PSF) cocktail consisting of IGF1, Bcl-XL, a caspase inhibitor, a mitochondrial pathway inhibitor and matrigel into the limbs of immune deficient mice, after induction of hindlimb ischemia. The PSF markedly prolonged the retention of the MSCs in the ischemic limb muscles as demonstrated by bioluminescence imaging. Using micro-computed tomography (micro-CT) to image the limb muscle vasculature in the mice nine weeks after the transplantation, we found that the mice transplanted with MSCs without PSF did not show a significant increase in the blood vessels in the ischemic limb compared to the non-transplanted control mice. In contrast, the mice transplanted with MSCs plus PSF showed a significant increase in the blood vessels, especially the larger and branching vessels, in the ischemic limb as compared to the control mice that did not receive MSCs. Thus, we demonstrated that prolonged retention of MSCs using PSF effectively promoted angiogenesis in ischemic animal limbs. This study highlights the importance of enhancing cell survival in the development of effective MSC therapies to treat vascular diseases.