Single cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia

Abstract

SUMMARYTherapeutic angiogenesis using mesenchymal stem/stromal cell grafts have shown modest and controversial effects in preventing amputation for patients with critical limb ischemia. Through single-cell transcriptomic analysis of human tissues, we identified CD271+progenitors specifically from subcutaneous adipose tissue (AT) as having the most prominent pro-angiogenic gene profile distinct from other stem cell populations. AT-CD271+progenitors demonstrated robustin vivoangiogenic capacity, over conventional adipose stromal cell grafts, characterized by long-term engraftment, augmented tissue regeneration, and significant recovery of blood flow in a xenograft model of limb ischemia. Mechanistically, the angiogenic capacity of CD271+progenitors is dependent on functional CD271 and mTOR signaling. Notably, the number and angiogenic capacity of CD271+progenitors was strikingly reduced in insulin resistant donors. Our study highlights the identification of AT-CD271+progenitors within vivosuperior efficacy for limb ischemia. Furthermore, we showcase comprehensive single-cell transcriptomics strategies for identification of suitable grafts for cell therapy.HIGHLIGHTSAdipose tissue stromal cells have a distinct angiogenic gene profile among human cell sources.CD271+progenitors in adipose tissue have a prominent angiogenic gene profile.CD271+progenitors show superior therapeutic capacities for limb ischemia.CD271+progenitors are reduced and functionally impaired in insulin resistant donors.GRAPHICAL ABSTRACT