Quiescence and self-renewal of muscle stem cells require a type 2 deiodinase-mediated cell-autonomous surge in intracellular thyroid hormone signaling.

Stem cells are critical for the regeneration and homeostasis of adult tissues. Thyroid hormone (TH), whose intracellular concentration is increased by type 2 deiodinase (D2), is involved in many cell functions but its role in quiescence is unknown. Here we show that D2 marks the quiescent stem cells in muscle and skin, and that its activity is required to maintain quiescence. Genetic D2-depletion in quiescent muscle stem cells triggers their spontaneous transition from G0 to a GAlert –like state. D2-depletion increases the proliferative potential of stem cells upon muscle injury, but impairs their self-renewal capacity, leading to depletion of the stem cell pool over time and regenerative failure. Mechanistically, TH sustains Notch signalling by directly promoting the expression of Notch receptors and their canonical target genes. In the acute setting, transient pharmacological inhibition of D2 accelerates muscle regeneration and skin wound healing by promoting stem cell expansion. In conclusion, D2-dependent sustained intracellular TH concentration is critical for maintaining stem cell quiescence and in regulating self-renewal. Overall design: To investigate the mechanisms by which D2 controls quiescence we performed RNA-seq analysis of freshly isolated quiescent muscle stem cells from 3 cD2KO mice versus 3 controls booth in resting conditions. Muscle stem cells were isolated from hindlimb muscles of 3-4 month old Pax7nGFP/+;Pax7+/+;Dio2Fl/Fl (control) and Pax7nGFP/+;Pax7-CreERT2/+;Dio2Fl/Fl (cD2KO) mice.