Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity

Abstract

The development of cell therapies to treat peripheral vascular disease has proven difficult because of the contribution of multiple cell types that coordinate revascularization. We characterized the vascular regenerative potential of transplanted human bone marrow (BM) cells purified by high aldehyde dehydrogenase (ALDH^hi) activity, a progenitor cell function conserved between several lineages. BM ALDH^hi cells were enriched for myelo-erythroid progenitors that produced multipotent hematopoietic reconstitution after transplantation and contained nonhematopoietic precursors that established colonies in mesenchymal-stromal and endothelial culture conditions. The regenerative capacity of human ALDH^hi cells was assessed by intravenous transplantation into immune-deficient mice with limb ischemia induced by femoral artery ligation/transection. Compared with recipients injected with unpurified nucleated cells containing the equivalent of 2- to 4-fold more ALDH^hi cells, mice transplanted with purified ALDH^hi cells showed augmented recovery of perfusion and increased blood vessel density in ischemic limbs. ALDH^hi cells transiently recruited to ischemic regions but did not significantly integrate into ischemic tissue, suggesting that transient ALDH^hi cell engraftment stimulated endogenous revascularization. Thus, human BM ALDH^hi cells represent a progenitor-enriched population of several cell lineages that improves perfusion in ischemic limbs after transplantation. These clinically relevant cells may prove useful in the treatment of critical ischemia in humans.