Abstract
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.
Highlights
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
We further show that Fam3a is secreted by myogenic cells and that treatment with recombinant Fam3a rescues the reduced mitochondrial respiration and defective myogenic commitment of Stat3-ablated muscle stem cells (MuSCs) both in vitro and in vivo during adult skeletal muscle repair
Common to several stem cell compartments, MuSC commitment and differentiation requires the induction of oxidative metabolism[2,3,9,10,11,12]
Summary
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. We show that myogenic cells secrete Fam3a, and exposure of Stat3ablated 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. MuSC transition between different functional stem cell states can be identified by the expression of myogenic markers, which are transcription factors dynamically expressed during MuSC myogenic lineage progression[13] This makes MuSCs a powerful tool for studying the mechanisms that regulate stem cell fate choices. We further show that Fam3a is secreted by myogenic cells and that treatment with recombinant Fam3a rescues the reduced mitochondrial respiration and defective myogenic commitment of Stat3-ablated MuSCs both in vitro and in vivo during adult skeletal muscle repair. This work positions the Stat3–Fam3a axis as a driver of mitochondrial respiration during MuSC commitment and differentiation and suggests that therapeutic interventions targeting this axis could be utilized to promote MuSC-mediated tissue repair
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