Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury

Daniel Jun-Kit Hu,Justin Elstrott,Heinrich Jasper,Jina Yun

doi:10.1038/s41467-021-27384-4

Abstract

Tissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues. How accurate stem cell positioning and localized integration of new cells into the damaged epithelium are achieved, however, remains unclear. Here, we show that enteroendocrine cells coordinate stem cell migration towards a wound in the Drosophila intestinal epithelium. In response to injury, enteroendocrine cells release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in intestinal stem cells, promoting actin-based protrusion formation and stem cell migration towards a wound. We find that this migratory behavior is closely linked to proliferation, and that it is required for efficient tissue repair during injury. Our findings highlight the role of non-canonical Wnt signaling in regeneration of the intestinal epithelium, and identify enteroendocrine cell-released ligands as critical coordinators of intestinal stem cell migration.

Highlights

Tissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues
Flies were infected with Erwinia carotovora carotovora 15 (Ecc15), a gram-negative bacterium that damages differentiated enterocytes, to induce a regenerative response (Fig. 1A)[39,40]
Our results uncover a mechanism by which EEs stimulate intestinal stem cell (ISC) migration towards an injured area in the intestinal epithelium (Fig. 6E)

Summary

Introduction

Tissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues. Enteroendocrine cells release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in intestinal stem cells, promoting actin-based protrusion formation and stem cell migration towards a wound We find that this migratory behavior is closely linked to proliferation, and that it is required for efficient tissue repair during injury. We demonstrate that Drosophila ISCs rapidly initiate migration after enteropathogen infection and after localized tissue damage by laser ablation This process is mediated by a signaling cascade relying on matrix-metalloproteinase (MMP) induction and Otk expression in EEs at the wound site, which in turn activates non-canonical Wnt signaling in ISCs, promoting the actin-dependent formation of lamellipodia, and migration of ISCs to the wound area. We propose that MMP-mediated cleavage of Otk in EEs at the wound is a critical signal promoting ISC migration toward the site of epithelial injury, ensuring efficient regeneration

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Results

Conclusion