Transcriptional regulation of intestinal epithelial homeostasis and regeneration

Student thesis: Doctoral ThesisDoctor of Philosophy


Intestinal stem cells (ISCs) reside at the bottom of intestinal crypts. They divide and give rise to early progenitor cells (+4/+5 cells) when entering the transitamplifying zone (TA), and eventually differentiate into various mature epithelial cell types. Wnt, Notch and Tgf-β/Bmp signalling pathways form gradient of expression along the crypt-villus axis and play a central role in regulating ISC homeostasis and lineage commitment. Despite the good understanding of the signalling pathways in regulating ISC self-renewal and fate decision, the underlying mechanism of the dynamic lineage selection and plasticity of the +4/+5 early progenitors remains largely unknown.

Here, we identify Arid3a as a novel regulator of intestinal epithelial cell differentiation and maturation. Arid3a is expressed at the early progenitors at +4/+5 cell positions and most differentiated cells with an expression gradient that accumulates at the tip of the villus. We show that Wnt signalling has an inhibitory role on the expression of Arid3a, while Tgf-β signalling promotes its expression. Intestinal epithelial-specific deletion of Arid3a leads to decreased numbers of proliferating TA cells at the upper crypt and a reduction of Wnt signalling which is associated with a moderate decrease of Paneth cell numbers. Interestingly, ISC numbers are not affected. Most importantly, loss of Arid3a perturbs the zonation programme of the entire intestinal epithelium. Expression analysis of the Arid3a cKO intestine showed a reduced gene signatures of committed cells at the upper crypt and a strong enrichment of mid-villus to villus-tip gene signatures of enterocytes, goblet, enteroendocrine and tuft cells. Our findings suggest that TA cells enter their differentiated states earlier at the expense of their proliferative capacity. Finally, using an irradiation mouse model, we show that loss of Arid3a impairs the regenerative process by altering the dynamics of proliferation and apoptosis.

We conclude that Arid3a drives maintenance of epithelial homeostasis across the crypt-villus axis and supports the regenerative capacity of the intestinal epithelium. Our work provides an important advancement in understanding the regulation of TA cells state and the transdifferentiation process in the intestinal epithelium.
Date of Award1 Feb 2023
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorVivian Li (Supervisor) & Karen Liu (Supervisor)

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