美国加州大学洛杉矶分校April D. Pyle课题组报道，再生的人类骨骼肌在体内形成了一个新兴的生态位来支持PAX7细胞。相关论文于2023年11月2日发表在《自然—细胞生物学》杂志上。

他们假设与小鼠卫星细胞(SCs)的竞争阻止了骨骼肌祖细胞(SMPCs)植入SC生态位，从而产生了与人类植入相容的SC消融小鼠。SC消融小鼠的单核RNA测序鉴定了在再生过程中缺乏表达Actc1的瞬时肌纤维亚型。同样，在SC消融的小鼠中，ACTC1+人肌纤维支持PAX7+ SMPCs增加，并且在再次损伤后，他们发现SMPCs现在可以重新填充到嵌合壁龛中。

为了证明ACTC1+肌纤维对支持PAX7 SMPCs至关重要，他们产生了caspase诱导的ACTC1耗尽人多能干细胞，在SMPC植入后，他们发现与非诱导对照相比，ACTC1+肌纤维减少了90%，PAX7细胞数量减少了100倍。他们使用空间RNA测序来确定驱动ACTC1+肌纤维和PAX7+ SMPCs之间在体内形成新生态位的关键因素。这表明，瞬时再生的人类肌纤维对于支持PAX7 SMPCs的体内新兴生态位形成至关重要。

据介绍，骨骼肌干细胞和祖细胞，包括来自人类多能干细胞(hPSCs)的细胞，为个性化治疗提供了一条途径，并且在体内很容易融合形成人-小鼠肌纤维。然而，SMPC不能有效地定植嵌合干细胞壁龛，而是与类似胎儿壁龛的人肌纤维结合。

附：英文原文

Title: Regenerating human skeletal muscle forms an emerging niche in vivo to support PAX7 cells

Author: Hicks, Michael R., Saleh, Kholoud K., Clock, Ben, Gibbs, Devin E., Yang, Mandee, Younesi, Shahab, Gane, Lily, Gutierrez-Garcia, Victor, Xi, Haibin, Pyle, April D.

Issue&Volume: 2023-11-02

Abstract: Skeletal muscle stem and progenitor cells including those derived from human pluripotent stem cells (hPSCs) offer an avenue towards personalized therapies and readily fuse to form human–mouse myofibres in vivo. However, skeletal muscle progenitor cells (SMPCs) inefficiently colonize chimeric stem cell niches and instead associate with human myofibres resembling foetal niches. We hypothesized competition with mouse satellite cells (SCs) prevented SMPC engraftment into the SC niche and thus generated an SC ablation mouse compatible with human engraftment. Single-nucleus RNA sequencing of SC-ablated mice identified the absence of a transient myofibre subtype during regeneration expressing Actc1. Similarly, ACTC1+ human myofibres supporting PAX7+ SMPCs increased in SC-ablated mice, and after re-injury we found SMPCs could now repopulate into chimeric niches. To demonstrate ACTC1+ myofibres are essential to supporting PAX7 SMPCs, we generated caspase-inducible ACTC1 depletion human pluripotent stem cells, and upon SMPC engraftment we found a 90% reduction in ACTC1+ myofibres and a 100-fold decrease in PAX7 cell numbers compared with non-induced controls. We used spatial RNA sequencing to identify key factors driving emerging human niche formation between ACTC1+ myofibres and PAX7+ SMPCs in vivo. This revealed that transient regenerating human myofibres are essential for emerging niche formation in vivo to support PAX7 SMPCs.

DOI: 10.1038/s41556-023-01271-0

Source: https://www.nature.com/articles/s41556-023-01271-0