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 6

D2KO improves the phenotype of mdx mice.

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D2KO improves the phenotype of mdx mice. (A) Representative H&E of T...
(A) Representative H&E of TA sections from mdx and mdx-D2KO mice. Scale bar: 100 μm. n = 9 mdx and mdx-D2KO mice. (B) Quantification of the percentage of fibers with central nuclei in mdx and mdx-D2KO mice. (C) Quantification of the CSA. (D) Representative IF staining of PAX7+ (scale bars: 100 μm) and quantification (right). (E) Relative mRNA levels of MyoD and myogenin. (F and G) Performance in 4-limb (F) and 2-limb (G) muscle strength hanging tests of controls (Ctr), mdx, and mdx-D2KO mice at 4 weeks of age. n = 10 Ctr, n = 15 mdx, and n = 12 mdx-D2KO mice. (H) Pax7 and Myh8 mRNA levels from muscles at different weeks of age. Data are presented as mean ± SEM of at least 3 technical replicates. n = 6 mdx and n = 6 mdx-D2KO mice. (I) Schematic of the D2-depleted MuSC transplantation assay. MuSC/GFP+ cells from WT (Pax7creERT2/+ D2+/+ R26mTmG) and cD2KO (Pax7creERT2/+ D2fl/fl R26mTmG) mice were transplanted into the TA muscle of a single recipient mdx mouse. n = 12 WT and n = 12 cD2KO recipient mdx mice. (J) Representative IF staining of green epifluorescent fibers of mdx mice xenografted as indicated. Laminin is in red. Scale bars: 100 μm. (K) Percentage of green epifluorescent fibers at 21 (upper) and 40 days (lower) following transplantation of MuSC/GFP cells from WT and cD2KO donors. (L) Quantification of the CSA (μm2) of green fibers 21 (upper) and 40 days (lower) after xenografting. Data are presented as mean ± SEM of at least 3 technical replicates; *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. Each point (in B, D–G, and K) represents the average of at least 3 technical replicates from each mouse.