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 2

Absence of D2 leads to faster proliferation of MuSCs and transiently accelerates muscle regeneration.

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Absence of D2 leads to faster proliferation of MuSCs and transiently acc...
(A) Schematic of the experimental design, in which mice were euthanized at 7 (B–E) and 21 days (F–I). n = 9 WT and n = 9 cD2KO mice (7 days); n = 8 WT and n = 8 cD2KO mice (21 days). (B) H&E staining of the TA sections. Scale bars: 100 μm. (C) Quantification of the CSA in B. (D) Representative IF staining of PAX7 (red) and MyoD (green) on TA sections. The arrows indicate PAX7+MyoD+ cells. Scale bars: 50 μm. (E) The number of PAX7–MyoD+, PAX7+MyoD+, and PAX7+MyoD– cells per mm2 in D. (F) H&E staining of the TA sections. Scale bars: 100 μm. (G) Quantification of the CSA. (H) Representative IF staining of PAX7 (red) and MyoD (green) on TA sections. The arrows indicate PAX7+MyoD+ cells. Scale bars: 50 μm. (I) The number of PAX7–MyoD+, PAX7+MyoD+, and PAX7+MyoD– cells per mm2 in H. 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.