Angiogenin released from ABCB5(+) MSCs Promotes Healing of Diabetic Wounds by triggering Angiogenesis

Diabetes mellitus is an urgent global health problem imposing a significant socioeconomic burden on societies. With high recurrence rates, non-healing wounds in diabetic patients are highly susceptible for necrosis due to ischemia and often progress to lower limb amputation. Severe angiopathy with reduced angiogenesis is a major driver for diabetes associated non-healing wounds. To dissect the underlying mechanisms, we here addressed the question whether administration of skin derived ABCB5+ MSCs, precursors of perivascular fibroblasts, can rescue suppressed angiogenesis and impaired wound healing in a full thickness wound model in diabetic mice. Employing RNA sequencing analysis, we found marked alterations in the global transcriptome of HUVECs following exposure of diabetic mimetic palmitate. GO analysis uncovered highly enriched genes linked to vascular complications in palmitate exposed HUVECs. Of note, fibroblasts treated either with palmitate or derived from diabetic mice - when co-cultured with healthy HUVECs - also severely suppressed angiogenesis. Blood vessel numbers were significantly reduced in db/db mice skin and wounds as determined by immunostaining against endothelial CD31. Interestingly, injection of ABCB5+MSCs around wounds rescued impaired angiogenesis and wound healing in db/ db mice. Secretome analysis of ABCB5+ MSCs uncovered the ribonuclease angiogenin to be mainly responsible for this. Silencing of angiogenin in ABCB5+ MSCs significantly reduced angiogenesis and delayed wound closure in diabetic db/db mice implying an unprecedented key role for angiogenin in skin regeneration. Its proangiogenic action is partly due to phosphorylation of the VEGF receptor. Angiogenin is significantly reduced in human chronic diabetic ulcers. These data highlight that the specific delivery of proangiogenic favoring molecules holds significant promise for further refining MSC-based therapies for non-healing diabetic foot ulcers.