Development, Aging and Regeneration Program at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Avidity Biosciences LLC, La Jolla, CA, 92037, USA.
Nat Commun. 2018 Sep 10;9(1):3670. doi: 10.1038/s41467-018-06068-6.
Fibro-adipogenic progenitors (FAPs) are currently defined by their anatomical position, expression of non-specific membrane-associated proteins, and ability to adopt multiple lineages in vitro. Gene expression analysis at single-cell level reveals that FAPs undergo dynamic transitions through a spectrum of cell states that can be identified by differential expression levels of Tie2 and Vcam1. Different patterns of Vcam1-negative Tie2 or Tie2 and Tie2/Vcam1-expressing FAPs are detected during neonatal myogenesis, response to acute injury and Duchenne Muscular Dystrophy (DMD). RNA sequencing analysis identified cell state-specific transcriptional profiles that predict functional interactions with satellite and inflammatory cells. In particular, Vcam1-expressing FAPs, which exhibit a pro-fibrotic expression profile, are transiently activated by acute injury in concomitance with the inflammatory response. Aberrant persistence of Vcam1-expressing FAPs is detected in DMD muscles or upon macrophage depletion, and is associated with muscle fibrosis, thereby revealing how disruption of inflammation-regulated FAPs dynamics leads to a pathogenic outcome.
纤维脂肪祖细胞（FAPs）目前通过其解剖位置、非特异性膜相关蛋白的表达以及在体外采用多种谱系的能力来定义。单细胞水平的基因表达分析表明，FAP 经历通过 Tie2 和 Vcam1 差异表达水平可识别的细胞状态谱的动态转变。在新生儿肌发生、急性损伤和 Duchenne 肌营养不良症（DMD）的反应过程中检测到不同模式的 Vcam1 阴性 Tie2 或 Tie2 和 Tie2/Vcam1 表达的 FAP。RNA 测序分析确定了细胞状态特异性转录谱，这些谱预测与卫星细胞和炎症细胞的功能相互作用。特别是，表达 Vcam1 的 FAP 表现出促纤维化的表达谱，在炎症反应伴随急性损伤时被短暂激活。在 DMD 肌肉或巨噬细胞耗竭时检测到表达 Vcam1 的 FAP 的异常持续存在，与肌肉纤维化相关，从而揭示了炎症调节的 FAP 动力学的破坏如何导致致病结果。
