Type 2 deiodinase–dependent surge in thyroid hormone controls muscle stem cell quiescence and self-renewal
Maria Angela De Stefano, Raffaele Ambrosio, Cristina Luongo, Tommaso Porcelli, Daniela Di Girolamo, Caterina Miro, Monica Dentice, Caterina Missero, Domenico Salvatore
Maria Angela De Stefano, Raffaele Ambrosio, Cristina Luongo, Tommaso Porcelli, Daniela Di Girolamo, Caterina Miro, Monica Dentice, Caterina Missero, Domenico Salvatore
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Research Article Endocrinology Metabolism

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

Abstract

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.

Authors

Maria Angela De Stefano, Raffaele Ambrosio, Cristina Luongo, Tommaso Porcelli, Daniela Di Girolamo, Caterina Miro, Monica Dentice, Caterina Missero, Domenico Salvatore

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Figure 1

D2 is highly expressed in qMuSCs, and its deletion favors cell activation.

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D2 is highly expressed in qMuSCs, and its deletion favors cell activatio...
(A) Representative IF of PAX7, D2, and laminin colocalization. Confocal images of PAX7 (green), D2-FLAG (red), laminin (white) and DAPI (blue) expression on cryosections of TA muscle from D2-FLAG mice. Scale bars: 2 μm. (B) Single myofibers with associated MuSCs were immunostained for PAX7 (green) and D2-FLAG (red). Scale bar: 50 μm. T = hours. (C) Schematic of the experimental design and representative IF staining for both D2 and D3 versus EdU in cultured fibers at 72 hours. EDL, extensor digitorum longus. Scale bar: 50 μm. At right, quantification of the percentage of D2+EdU+ and D3+EdU+ cells. n = 9 mice for D2 and n = 9 mice for D3. (D) Schematic of the experimental design and mouse model used. (E) Quantification of the percentage of PAX7+MyoD–, PAX7+MyoD+, and PAX7–MyoD+ cells on isolated myofibers, after in vivo TAM induction, at different time points. n = 5 WT and n = 4 cD2KO mice. Data are presented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001 using a Mann-Whitney test when comparing 2 conditions and 2-way ANOVA when comparing multiple conditions.