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 triggers their transition from G0 to a GAlert-like state. This increases the proliferative potential of the stem cells, but impairs their self-renewal capacity, leading to depletion of the stem cell pool and regenerative failure over time. Mechanistically, TH sustains Notch signaling, and active Notch overexpression partially rescues D2-depletion. Transient pharmacological inhibition of D2 accelerates 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.