DE STEFANO, MARIA ANGELA (2021) "Thyroid Hormone Acts as a Master Regulator of Quiescence and Self-Renewal in Stem Cells". [Tesi di dottorato]

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Abstract

Stem cells are critical for the regeneration and homeostasis of adult tissues. Thyroid hormone (TH), whose intracellular concentration is regulated by deiodinases (D2 and D3), is implicated in stem cell function and lineage progression. The aim of this study was to determine the role of TH and its intracellular metabolism in stem cell quiescence, which is still a poorly understood condition. Here we show that D2 expression marks quiescent stem cells in muscle and skin. Acute D2-depletion in quiescent muscle stem cells triggers their spontaneous transition from G0 into a GAlert state. Upon muscle injury, D2-depletion increases the proliferative potential of activated precursor cells but impairs self-renewal of progenitors returning to quiescence. Genetic D2-depletion leads, in the long run or upon multiple injuries, to depletion of the stem cell pool and regenerative failure. Mechanistically, D2-produced TH sustains Notch signalling by directly promoting the expression of Notch receptors and their canonical target genes. In normal and pathological settings, transient drug-induced D2 blocking accelerates muscle regeneration and skin wound healing. In conclusion, a D2-induced increased intracellular TH concentration is critical in maintaining stem cell quiescence and in regulating self-renewal. In this context, tissue-specific manipulation of TH may be an innovative therapeutic tool in the field of regenerative medicine.

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