Dai Qunsheng, Wan Changxin, Xu Yueyuan, Fei Kaileen, Olivere Lindsey A, Garrett Brianna, Akers Leo, Peters Derek, Otto James, Kontos Christopher D, Ji Zhiceng, Diao Yarui, Southerland Kevin W
Division of Vascular and Endovascular Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA.
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
bioRxiv. 2024 Jul 11:2024.07.08.602430. doi: 10.1101/2024.07.08.602430.
Skeletal muscle health and function is a critical determinant of clinical outcomes in patients with peripheral arterial disease (PAD). Herein, we identify fatty infiltration, the ectopic deposition of adipocytes in skeletal muscle, as a histological hallmark of end-stage PAD, also known as chronic limb threatening ischemia (CLTI). Leveraging single cell transcriptome mapping in mouse models of PAD, we identify a pro-adipogenic mesenchymal stromal cell population marked by expression of Vcam1 (termed Vcam1+ FAPs) that expands in the ischemic limb. Mechanistically, we identify Sfrp1 and Nr3c1 as regulators of Vcam1+ FAP adipogenic differentiation. Loss of Sfrp1 and Nr3c1 impair Vcam1+ FAP differentiation into adipocytes . Finally, we show that Vcam1+ FAPs are enriched in human CLTI patients. Collectively, our results identify a pro-adipogenic FAP subpopulation in CLTI patients and provide a potential therapeutic target for muscle regeneration in PAD.
骨骼肌健康与功能是外周动脉疾病（PAD）患者临床预后的关键决定因素。在此，我们确定脂肪浸润，即脂肪细胞在骨骼肌中的异位沉积，是终末期PAD（也称为慢性肢体威胁性缺血，CLTI）的组织学标志。利用PAD小鼠模型中的单细胞转录组图谱，我们鉴定出一个以Vcam1表达为特征的促脂肪生成间充质基质细胞群体（称为Vcam1+ FAPs），该群体在缺血肢体中扩增。从机制上讲，我们确定Sfrp1和Nr3c1是Vcam1+ FAP脂肪生成分化的调节因子。Sfrp1和Nr3c1的缺失会损害Vcam1+ FAP向脂肪细胞的分化。最后，我们表明Vcam1+ FAPs在人类CLTI患者中富集。总体而言，我们的结果确定了CLTI患者中一个促脂肪生成的FAP亚群，并为PAD中的肌肉再生提供了一个潜在的治疗靶点。
