31 May 2021

UNDERSTANDING OF THE PROCESSES GOVERNING CELLULAR REPROGRAMMING DURING INTESTINAL REGENERATION

review

The field of intestinal regenerative biology has so far primarily studied the induction phases of tissue regeneration, and consequently the process of resolution of the repair-response allowing return to epithelial homeostasis remains an enigma.

Current Opinion in Genetics & Development, Volume 70, October 2021, Pages 40-47 https://doi.org/10.1016/j.gde.2021.05.005

Review by Hjalte Larsen and Kim B. Jensen

The field of intestinal regenerative biology has so far primarily studied the induction phases of tissue regeneration, and consequently the process of resolution of the repair-response allowing return to epithelial homeostasis remains an enigma.

The intestine is a vital organ mediating absorption of nutrients and water. Following tissue damage, the intestine mounts a remarkable regenerative response by reprogramming cellular identity to facilitate reinstatement of homeostasis. In this review postdoctoral scientist Hjalte Larsen and Professor Kim B. Jensen looked at recent advances within intestinal regenerative biology and the emerging concept of fetal-like reprogramming, in which the adult intestinal epithelium transiently enters a repair-associated state reminiscent of ontologically pre-existing stages. In this review they have focused on molecular mechanisms governing reprogramming of cellular identity via epithelial-mesenchymal crosstalk, and how novel approaches in organoid technologies enable identification and characterization of cell-autonomous repair responses within epithelial cells. Transitioning from the single-cell level to tissue scale, the authors discussed clonal selection following regeneration and associated pathological repercussions such as cancer and chronic inflammatory diseases.

“Investigating how occupancy of vacant stem cell niches might drive resolution of repair, and how reinstatement of proper tissue architecture following severe tissue destruction is coordinated with resolution of the reprogrammed state can potentially offer new therapeutic strategies.” -  Hjalte Larsen

Given the role of YAP1 in activating fetal-like reprogramming, and the well-established role of YAP1/TAZ as sensors of mechanical cues and cell crowding, it seems plausible that the increasing cell density following wound closure at least partly forces exit from the reprogrammed state. Gaining a deeper understanding of regeneration resolution could offer possibilities for controlling this phase of the injury response, putatively preventing the transition from acute to chronic inflammation and hence preventing occurrence of tissue fibrosis and other symptoms associated with this debilitating persistent pathological state.

Image: Organization of the intestinal epithelium.

“By advancing our understanding of these pertinent questions, the field of regenerative intestinal biology moves closer towards realizing the promise of translating findings from basic science to the clinic, benefitting the increasing number of patients suffering from inflammatory bowel diseases.” – Professor Kim B. Jensen

The authors went through several studies which highlight the wealth of insight gained in the recent years leading to a significant advancement of our understanding of the processes governing cellular reprogramming during intestinal regeneration. Emerging from these studies is the concept of fetal-like reprogramming, in which the adult intestinal epithelium transiently adopts characteristics of more primitive stages of intestinal ontogeny following injury.

With an expanding list of cells capable of contributing to tissue regeneration, cellular reprogramming seems a common process that can be elicited in diverse cell types upon multi-level integration of instructive signals.

Enabled by the development of new advances within single-cell profiling technologies, organoid culture and genome engineering, the field of intestinal regenerative biology is entering an exciting era where it will be possible to decipher whether the diverse array of reprogramming-competent cells utilize convergent pathways to facilitate the re-entry into the stem cell state, and how these processes are molecularly orchestrated.” -  Professor Kim B. Jensen

With a current epithelial-centric view of fetal-like reprogramming, it will be interesting to expand the concepts of this transient return to more primitive stages to uncover whether fetal-like reprogramming is a phenomenon employed at multiple levels to also encompass reacquisition of the morphological remodeling driving normal tissue development in the epithelium as well as in the stroma.

Read more about the Jensen group