| Background: Therapeutic angiogenesis of stem cell transplantation for ischemic disease are currently limited by low level of the cells survival rate, and then the deficiency of the angiogenic factors secreted by the cell. The peroxisome proliferator activated receptor-γcoactivator-1α(PGC-1α), a key regulator linking between angiogenesis and metabolism processes, may provide a new stem cell therapeutic strategy for ischemic disease. We performed this study to examine whether PGC-1αcould enhance engraftment and angiogenesis of mesenchymal stem cells (MSCs) in diabetic hindlimb ischemia.Methods:With an adenoviral vector encoding green fluorescent protein (GFP) and PGC-1α, we engineered the overexpression of PGC-1αwithin MSCs.And then we test the survivability and angiogenesis of the MSCs modified with gene under the ischemia environment in vitro and in vivo.Results:1. Under the condition of hypoxia concomitant with serum deprivation, the overexpression of PGC-1αin MSCs resulted in a more expression of HIF-1α, a higher ratio of Bcl-2/Bax and a less of caspase3 compared with the controls, followed by an increased survival rate and an elevated expression level of several proangiogenic factors in MSCs.2. After establishment of the diabetic rat lower limb ischemia model, rats were randomly grouped: PGC-1α-MSC group (PGC-1α-MSCs injection), GFP-MSC group (GFP-MSCs injection), MSC group (MSCs injection), and group PBS (PBS injection). Five days after transplantation,the survival number of PGC-1α-MSCs was significantly higher than that of GFP-MSCs.And angiogenesis factors expression of ischemia muscle in PGC-1αgroup was the highest, followed by the MSC group, GFP-MSC group, PBS group finally.Fourteen days after transplantation, MSCs modified with PGC-1αcould significantly increase the blood perfusion and capillary density of ischemic hindlimb in the diabetic rats and decrease the gangrene rate of ischemic hindlimb.Conclusion: We identified for the first time that over expression of PGC-1αmay enhance MSCs resistance to apoptosis and promotes angiogenesis potential of the MSCs directly or indirectly by Bcl-2 / Bax pathway and HIF pathway, could increase the survival number of MSCs and promote the paracrine of proangiogenic factors from MSCs in ischemic hindlimb, which may result in the enhanced engraftment and angiogenesis of MSCs in diabetic ischemic hindlimb. |
