Type 2 deiodinase-dependent surge in thyroid hormone controls muscle stem cell quiescence and self-renewal

Stem cells are critical for the homeostasis of adult tissues. Thyroid hormone (TH), whose intracellular concentration is increased by type 2 deiodinase (D2), is involved in many functions, but its role in quiescence is unknown. Here, we show that D2 marks quiescent stem cells in muscle and skin. Genetic D2 depletion in quiescent muscle stem cells triggered their transition from a G0 to a GAlert-like state. This increased the proliferative potential of the stem cells but impaired their self-renewal capacity, leading to depletion of the stem cell pool and regenerative failure over time. Mechanistically, TH sustained Notch signaling, and active Notch overexpression partially rescued D2 depletion. Transient pharmacological inhibition of D2 accelerated muscle regeneration and skin wound healing by promoting stem cell expansion. In conclusion, we show that D2 is a critical metabolic enzyme in maintaining stem cell quiescence and in regulating self-renewal.