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bioRxiv · 10.1101/2023.02.09.527726

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

Inoue, O.·Goten, C.·Hashimuko, D.·Yamaguchi, K.·Takeda, Y.·Nomura, A.·Ootsuji, H.·Takashima, S.·Iino, K.·Takemura, H.·Halurkar, M.·Lim, H.-W.·Hwa, V.·Sanchez-Gurmaches, J.·Usui, S.·Takamura, M.
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Abstract

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 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 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 was 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. HIGHLIGHTSO_LIAdipose tissue stromal cells have a distinct angiogenic gene profile among human cell sources. C_LIO_LICD271+ progenitors in adipose tissue have a prominent angiogenic gene profile. C_LIO_LICD271+ progenitors show superior therapeutic capacities for limb ischemia. C_LIO_LICD271+ progenitors are reduced and functionally impaired in insulin resistant donors. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/527726v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@1b5e1aorg.highwire.dtl.DTLVardef@bf2c34org.highwire.dtl.DTLVardef@ef0e68org.highwire.dtl.DTLVardef@9aee1f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Inoue, O., Goten, C., Hashimuko, D., Yamaguchi, K., Takeda, Y., Nomura, A., Ootsuji, H., Takashima, S., Iino, K., Takemura, H., Halurkar, M., Lim, H.-W., Hwa, V., Sanchez-Gurmaches, J., Usui, S., Takamura, M.. 2023-02-10. Single cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia. https://doi.org/10.1101/2023.02.09.527726

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