A Combination of Distinct Vascular Stem/Progenitor Cells for Neovascularization and Ischemic Rescue

Abstract

BACKGROUND: Peripheral vascular disease remains a leading cause of vascular morbidity and mortality worldwide despite advances in medical and surgical therapy. Besides traditional approaches, which can only restore blood flow to native arteries, an alternative approach is to enhance the growth of new vessels, thereby facilitating the physiological response to ischemia. METHODS: The Actin CreER /R26 VT2/GK3 Rainbow reporter mouse was used for unbiased in vivo survey of injury-responsive vasculogenic clonal formation. Prospective isolation and transplantation were used to determine vessel-forming capacity of different populations. Single-cell RNA-sequencing was used to characterize distinct vessel-forming populations and their interactions. RESULTS: Two populations of distinct vascular stem/progenitor cells (VSPCs) were identified from adipose-derived mesenchymal stromal cells: VSPC1 is CD45-Ter119-Tie2+PDGFRa-CD31+CD105 high Sca1 low , which gives rise to stunted vessels (incomplete tubular structures) in a transplant setting, and VSPC2 which is CD45-Ter119-Tie2+PDGFRa+CD31-CD105 low Sca1 high and forms stunted vessels and fat. Interestingly, cotransplantation of VSPC1 and VSPC2 is required to form functional vessels that improve perfusion in the mouse hindlimb ischemia model. Similarly, VSPC1 and VSPC2 populations isolated from human adipose tissue could rescue the ischemic condition in mice. CONCLUSIONS: These findings suggest that autologous cotransplantation of synergistic VSPCs from nonessential adipose tissue can promote neovascularization and represents a promising treatment for ischemic disease.

New Twist in Cell Therapy for the Treatment of Severe Ischemia

“…Among tested cell therapy approaches have been intra-arterial and intramuscular injections of several types of adult stem cell populations, such as circulating endothelial progenitor cells and bone marrow and adipose-derived stem cells, but the results at best have been very modest and often attributed to paracrine effects from factors released by the administered cells rather than regeneration of functional blood vessels capable of increasing blood perfusion in the ischemic limbs. 1 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Zhao et al 6 report a new approach for vascular stem/progenitor cell (VSPC) therapy to induce neovascularization and rescue of ischemic hind limbs in mice. They use an elaborate Rainbow reporter mouse model and transplantation of cell sorting-isolated angiogenic mesenchymal stromal cells (MSCs) to show vesselforming capacity of specific MSC subfractions in mice (Figure).…”