Thyroid hormone signaling in the intestinal stem cells and their niche

Abstract

Several studies emphasized the function of the thyroid hormones in stem cell biology. These hormones act through the nuclear hormone receptor TRs, which are T3-modulated transcription factors. Pioneer work on T3-dependent amphibian metamorphosis showed that the crosstalk between the epithelium and the underlying mesenchyme is absolutely required for intestinal maturation and stem cell emergence. With the recent advances of powerful animal models and 3D-organoid cultures, similar findings have now begun to be described in mammals, where the action of T3 and TRα1 control physiological and cancer-related stem cell biology. In this review, we have summarized recent findings on the multiple functions of T3 and TRα1 in intestinal epithelium stem cells, cancer stem cells and their niche. In particular, we have highlighted the regulation of metabolic functions directly linked to normal and/or cancer stem cell biology. These findings help explain other possible mechanisms by which TRα1 controls stem cell biology, beyond the more classical Wnt and Notch signaling pathways.

Keywords: Colon cancer; Intestinal epithelium; Stem cell; Stem cell niche; Thyroid hormone; Thyroid hormone receptor.

Fig. 1

TRα1 structure and mode of action. A Modular organization of the TRα1 nuclear receptor, including DNA-binding (DBD) and ligand-binding (LBD) domains. A/B, C, D and E indicate the typical structural domains of the nuclear receptors. B Typical organization of thyroid hormone-responsive elements (TREs) on target genes constituted by two repetitions of half-sites organized in different manners, as indicated. C Model of TR action on target genes. For a gene positively regulated by T3, in the absence of T3, co-repressors are recruited resulting in the inhibition of transcription. Upon T3 binding, co-activators bind to TR inducing transcription. The figure was created with BioRender.com (agreement number: QC23PTXLWH)

Fig. 2

Functional organization of the small intestine and colon epithelia. Organization of the intestinal mucosa in the small intestine (upper panel) and colon (middle panel), showing the vertical epithelial axis. At the bottom of the axis reside stem/progenitor cells while in the higher part of the vertical axis are located differentiated cells. It is interesting to note that TRα1 has a gradient of expression similar to Wnt and Notch pathway activities, while the BMP pathway presents an opposite gradient. In the bottom panel are depicted the different cell types present in the mucosa, including epithelial and mesenchymal-derived cells. The Figure was created with BioRender.com (agreement number: QC23PTXLWH)

Fig. 3

Proposed models recapitulating the integration of classical signaling and metabolic pathways depending on TH/TRα1 in intestinal crypts and colon cancer cells. A Differential outcome in SCs or in Paneth cells in response to T3, possibly inducing metabolic shifts. Accumulating data suggest that T3 through the TRα1 receptor modulates the stemness in crypts via regulation of the Wnt and Notch pathways. However, recent data also point to the induction of metabolic challenges stimulated by high glucose and high lipid metabolism, acting on the balance between self-renewal and differentiation [8, 32, 37]. Importantly, T3 also induces an increase of Paneth cells in the intestinal crypts [10]. Paneth cells are well known to act on stemness through Wnt and Notch, but also to produce lactate that once up-taken by SCs contributes to the oxidative phosphorylation (OXPHOS) metabolic pathway [115], participating in the maintenance of the stem phenotype. B Overview of the integrated glucose and lipid metabolism in the intestinal SCs under T3 treatment. We speculate that T3 might mimic a high glycolysis and high lipolysis condition increasing OXPHOS. Upon oxidation of fatty acids, stimulated OXPHOS can induce reactive oxygen species (ROS) and p38 expression. The stemness, stimulated by Wnt and Notch, or the differentiation induced by ROS/p38, depend on the balance between these two events. C Integrated view of the action of T3/TRα1 in a cancer context. Adipocytes are strongly mobilized in the cancer environment and considered as part of the cancer stem cell niche [56, 149, 150], releasing high levels of lipids that can be absorbed by cancer cells. The T3-induced transcriptional program includes genes involved in fatty acid oxidation, OXPHOS, and stemness together with mitochondrial turnover. The balance between these major events determines the extent of stem potential versus their differentiation. The Figure was created with BioRender.com (agreement number: PO23PTXM00)