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Microvascular lesion in diabetic peripheral arterial disease (PAD) still cannot be resolved by current surgical and interventional technique. Endothelial cells have the therapeutic potential to cure microvascular lesion. To evaluate the efficacy and immune-regulatory impact of intra-arterial infusion of autologous CD133+ cells, we recruited 53 patients with diabetic PAD (27 of CD133+ group and 26 of control group). CD133+ cells enriched from patients’ PB-MNCs were reinfused intra-arterially. The ulcer healing followed up till 18 months was 100% (3/3) in CD133+ group and 60% (3/5) in control group. The amputation rate was 0 (0/27) in CD133+ group and 11.54% (3/26) in control group. Compared with the control group, TcPO2 and ABI showed obvious improvement at 18 months and significant increasing VEGF and decreasing IL-6 level in the CD133+ group within 4 weeks. A reducing trend of proangiogenesis and anti-inflammatory regulation function at 4 weeks after the cells infusion was also found. These results indicated that autologous CD133+ cell treatment can effectively improve the perfusion of morbid limb and exert proangiogenesis and anti-inflammatory immune-regulatory impacts by paracrine on tissue microenvironment. The CD133+ progenitor cell therapy may be repeated at a fixed interval according to cell life span and immune-regulatory function. [ABSTRACT FROM AUTHOR]

Microvascular lesion in diabetic peripheral arterial disease (PAD) still cannot be resolved by current surgical and interventional technique. Endothelial cells have the therapeutic potential to cure microvascular lesion. To evaluate the efficacy and immune-regulatory impact of intra-arterial infusion of autologous CD133(+) cells, we recruited 53 patients with diabetic PAD (27 of CD133(+) group and 26 of control group). CD133(+) cells enriched from patients' PB-MNCs were reinfused intra-arterially. The ulcer healing followed up till 18 months was 100% (3/3) in CD133(+) group and 60% (3/5) in control group. The amputation rate was 0 (0/27) in CD133(+) group and 11.54% (3/26) in control group. Compared with the control group, TcPO2 and ABI showed obvious improvement at 18 months and significant increasing VEGF and decreasing IL-6 level in the CD133(+) group within 4 weeks. A reducing trend of proangiogenesis and anti-inflammatory regulation function at 4 weeks after the cells infusion was also found. These results indicated that autologous CD133(+) cell treatment can effectively improve the perfusion of morbid limb and exert proangiogenesis and anti-inflammatory immune-regulatory impacts by paracrine on tissue microenvironment. The CD133(+) progenitor cell therapy may be repeated at a fixed interval according to cell life span and immune-regulatory function.

Endothelial damage is strongly associated with cardiovascular diseases such as atherosclerosis. Bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial homeostasis and contribute to re-endothelialization of injured vessels as well as revascularization of ischemic tissues. MicroRNAs (miRNAs) have been reported to regulate EPC biological functions. In this study, we found that EPCs of atherosclerosis patients and EPCs exposed to hypoxia have increased expression of miRNA-21 (miR-21) as well as diminished ability to proliferate. MiR-21 knockdown rescued hypoxia-induced growth arrest in EPCs. Next, we used a luciferase reporter assay to demonstrate that miR-21 downregulates the expression of WW domain-containing protein 1 (WWP1), a negative regulator of TGFβ signaling, by directly targeting the 3'-UTR of WWP1. Finally, miR-21 overexpression or WWP1 knockdown in EPCs significantly activates the TGFβ signaling pathway and inhibits cell proliferation. Taken together, our results indicate that miR-21 suppresses EPC proliferation by activating the TGFβ signaling pathway via downregulation of WWP1. These findings may help the development of strategies to enhance the vitality of EPCs for therapeutic applications.