A genetic framework controlling the differentiation of intestinal stem cells during regeneration in Drosophila

Abstract

The speed of stem cell differentiation has to be properly coupled with self-renewal, both under basal conditions for tissue maintenance and during regeneration for tissue repair. Using the Drosophila midgut model, we analyze at the cellular and molecular levels the differentiation program required for robust regeneration. We observe that the intestinal stem cell (ISC) and its differentiating daughter, the enteroblast (EB), form extended cell-cell contacts in regenerating intestines. The contact between progenitors is stabilized by cell adhesion molecules, and can be dynamically remodeled to elicit optimal juxtacrine Notch signaling to determine the speed of progenitor differentiation. Notably, increasing the adhesion property of progenitors by expressing Connectin is sufficient to induce rapid progenitor differentiation. We further demonstrate that JAK/STAT signaling, Sox21a and GATAe form a functional relay to orchestrate EB differentiation. Thus, our study provides new insights into the complex and sequential events that are required for rapid differentiation following stem cell division during tissue replenishment.

Author summary

Adult tissue/organ function is maintained by stem cells. Key question in stem cell biology is how the pool of stem cells can be robustly expanded yet timely contracted through differentiation according to the need of a tissue. Over the last years, the mechanisms underlying stem cell activation have been extensively studied, while the genetic control of progenitor differentiation, especially during regeneration, is still poorly understood. Using the fruit fly Drosophila midgut as model, we investigate the cellular changes and the genetic program required for efficient progenitor differentiation during intestinal regeneration. We first detect the presence of extended cell-cell contact between a stem cell and its differentiating daughter in regenerating intestine, compared to homeostatic conditions. The extended cell-cell contact is consolidated by cell adhesion molecules and enhances Notch signaling in the differentiating progenitors leading to their fast differentiation into enterocytes. We further uncover a genetic program, involving the JAK/STAT and Dpp signaling, the Sox21a and GATAe transcription factors, which acts in the differentiating progenitors to instruct their terminal differentiation. Thus, our study presents an integrated view of stem cell differentiation during tissue regeneration and the findings here are likely to apply to mammals.