Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901N Torrey Pines Road, La Jolla, CA, 92037, USA.
Mammalian Genetics Unit, MRC Harwell Institute, Oxfordshire, OX11 0RD, UK.
Nat Commun. 2019 Apr 17;10(1):1796. doi: 10.1038/s41467-019-09746-1.
Metabolic reprogramming is an active regulator of stem cell fate choices, and successful stem cell differentiation in different compartments requires the induction of oxidative phosphorylation. However, the mechanisms that promote mitochondrial respiration during stem cell differentiation are poorly understood. Here we demonstrate that Stat3 promotes muscle stem cell myogenic lineage progression by stimulating mitochondrial respiration in mice. We identify Fam3a, a cytokine-like protein, as a major Stat3 downstream effector in muscle stem cells. We demonstrate that Fam3a is required for muscle stem cell commitment and skeletal muscle development. We show that myogenic cells secrete Fam3a, and exposure of Stat3-ablated muscle stem cells to recombinant Fam3a in vitro and in vivo rescues their defects in mitochondrial respiration and myogenic commitment. Together, these findings indicate that Fam3a is a Stat3-regulated secreted factor that promotes muscle stem cell oxidative metabolism and differentiation, and suggests that Fam3a is a potential tool to modulate cell fate choices.
代谢重编程是干细胞命运选择的主动调节剂，不同隔室中成功的干细胞分化需要诱导氧化磷酸化。然而，促进干细胞分化过程中线粒体呼吸的机制还知之甚少。在这里，我们证明 Stat3 通过刺激小鼠肌肉干细胞中的线粒体呼吸来促进肌肉干细胞的成肌谱系进展。我们确定 Fam3a，一种细胞因子样蛋白，是肌肉干细胞中 Stat3 的主要下游效应物。我们证明 Fam3a 是肌肉干细胞分化为成肌细胞和骨骼肌发育所必需的。我们表明，成肌细胞分泌 Fam3a，体外和体内向 Stat3 缺失的肌肉干细胞中添加重组 Fam3a 可挽救其在线粒体呼吸和成肌细胞分化中的缺陷。总之，这些发现表明 Fam3a 是一种 Stat3 调节的分泌因子，可促进肌肉干细胞的氧化代谢和分化，并表明 Fam3a 是调节细胞命运选择的潜在工具。
