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

Therapeutic 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 identify 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 demonstrate robust in vivo angiogenic 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 are strikingly reduced in insulin-resistant donors. Our study highlights the identification of AT-CD271⁺ progenitors with in vivo superior efficacy for limb ischemia. Furthermore, we showcase comprehensive single-cell transcriptomics strategies for identification of suitable grafts for cell therapy.