ABSTRACT
The thyroid hormone T3 and its nuclear receptor TRα1 control gut development and homeostasis through the modulation of intestinal crypt cell proliferation. Despite increasing data, in-depth analysis on their specific action on intestinal stem cells is lacking. By using ex vivo 3D organoid cultures and molecular approaches, we observed early responses to T3 involving the T3-metabolizing enzyme Dio1 and the transporter Mct10, accompanied by a complex response of stem cell- and progenitor-enriched genes. Interestingly, specific TRα1 loss-of-function (inducible or constitutive) was responsible for low ex vivo organoid development and impaired stem cell activity. T3 treatment of animals in vivo not only confirmed the positive action of this hormone on crypt cell proliferation but also demonstrated its key action in modulating the number of stem cells, the expression of their specific markers and the commitment of progenitors into lineage-specific differentiation. In conclusion, T3 treatment or TRα1 modulation has a rapid and strong effect on intestinal stem cells, broadening our perspectives in the study of T3/TRα1-dependent signaling in these cells.
Subject(s)
Cell Proliferation , Intestines , Signal Transduction , Stem Cells/metabolism , Thyroid Hormone Receptors alpha/metabolism , Triiodothyronine/metabolism , Amino Acid Transport Systems, Neutral/genetics , Amino Acid Transport Systems, Neutral/metabolism , Animals , Female , Iodide Peroxidase/genetics , Iodide Peroxidase/metabolism , Male , Mice , Mice, Transgenic , Stem Cells/cytology , Thyroid Hormone Receptors alpha/genetics , Triiodothyronine/geneticsABSTRACT
The gastrointestinal tract is a well-characterized target of thyroid hormones and thyroid hormone nuclear receptors TRs, as extensively described in the literature. The paradigm is its important remodelling in amphibians during thyroid hormone-dependent metamorphosis. Interestingly, several studies have described the conservation of this hormonal signal during intestinal development in mammals. Additional data suggested that it may also play a role in intestinal homeostasis, stem cell physiology and progenitor commitment as well as in tumour development. It is worth underlining that in the mammalian intestine the functionality of the TRα1 receptor is coordinated and integrated with other signalling pathways, such as Wnt and Notch, specifically at the level of stem/progenitor cell populations. Here, we summarize these data and concepts and discuss this new role for thyroid hormones and the TRα1 receptor in the biology of intestinal epithelial precursor cells.