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

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 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.

SUBMITTER: Inoue O

PROVIDER: S-EPMC10772587 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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

Inoue Oto O Goten Chiaki C Hashimuko Daiki D Yamaguchi Kosei K Takeda Yusuke Y Nomura Ayano A Ootsuji Hiroshi H Takashima Shinichiro S Iino Kenji K Takemura Hirofumi H Halurkar Manasi M Lim Hee-Woong HW Hwa Vivian V Sanchez-Gurmaches Joan J Usui Soichiro S Takamura Masayuki M

Cell reports. Medicine 20231201 12

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 angiog ...[more]

PMID: 38118404

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Project description:Older patients are thought to tolerate acute ischemia more poorly than younger patients. Since aging may depress both angiogenesis and arteriogenesis, we determined the effects of age on both angiogenesis and arteriogenesis in a model of severe acute limb ischemia.Young adult (3-months-old) and aged (18-months-old) C57BL/6 mice underwent right common iliac artery and vein ligation and transection. Data were collected on days 0, 7, and 14. Perfusion was measured with a laser Doppler scan and compared to the contralateral limb. Functional deficits were evaluated with the Tarlov scale. Capillary density and endothelial progenitor cell (EPC) number were determined by direct counting lectin-positive/alpha-actin-negative cells and VEGFR2/CXCR4 dually-positive cells, respectively; angiography was performed to directly assess arteriogenesis.Young adult and aged mice had a similar degree of decreased perfusion after iliac ligation (young, n = 15: 20.4 +/- 1.9%, vs aged, n = 20: 19.6 +/- 1.3%; P = .72, analysis of variance [ANOVA]); however, young mice recovered faster and to a greater degree than aged mice (day 7, 35 +/- 6% vs 17 +/- 4%, P = .046; day 14, 60 +/- 5% vs 27 +/- 7%, P = .0014). Aged mice had worse functional recovery by day 14 compared to young mice (2.3 +/- 0.3 vs 4.3 +/- 0.4; P = .0021). Aged mice had increased capillary density (day 7, 12.9 +/- 4.4 vs 2.8 +/- 0.3 capillaries/hpf; P = .02) and increased number of EPC incorporated into the ischemic muscle (day 7, 8.1 +/- 0.9 vs 2.5 +/- 1.9 cells; P = .007) compared to young mice, but diminished numbers of collateral vessels to the ischemic limb (1 vs 9; P = .01), as seen on angiography.After severe hind limb ischemia, aged animals become ischemic to a similar degree as young animals, but aged animals have significantly impaired arteriogenesis and functional recovery compared to younger animals. These results suggest that strategies to stimulate arteriogenesis may complement those that increase angiogenesis, and may result in improved relief of ischemia.

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

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Single-cell transcriptomics identifies adipose tissue CD271<sup>+</sup> progenitors for enhanced angiogenesis in limb ischemia.

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

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Single-cell transcriptomics identifies adipose tissue CD271&lt;sup&gt;+&lt;/sup&gt; progenitors for enhanced angiogenesis in limb ischemia.

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OmicsDI is part of the ELIXIR infrastructure

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

Single-cell transcriptomics identifies adipose tissue CD271<sup>+</sup> progenitors for enhanced angiogenesis in limb ischemia.