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

AbstractTissue 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.

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

10.1101/2021.09.15.460565 ◽

2021 ◽

Author(s):

Heinrich Jasper ◽

Daniel Jun-Kit Hu ◽

Jina Yun ◽

Justin Elstrott

Keyword(s):

Stem Cell ◽

Wnt Signaling ◽

Intestinal Epithelium ◽

Cell Activation ◽

Intestinal Stem Cells ◽

Canonical Wnt Signaling ◽

Stem Cell Migration ◽

Cell Positioning ◽

Canonical Wnt

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, EEs release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in ISCs, promoting actin-based protrusion formation and ISC migration towards a wound. We find that this migratory behavior is closely linked to ISC 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 EE-released ligands as critical coordinators of ISC migration.

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WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: Augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates

International Journal of Molecular Medicine ◽

10.3892/ijmm.19.1.197 ◽

2007 ◽

Cited By ~ 1

Author(s):

Masuko Katoh ◽

Masaru Katoh

Keyword(s):

Stem Cells ◽

Wnt Signaling ◽

Notch Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Negative Regulation ◽

Intestinal Stem Cells ◽

Regulation System ◽

Canonical Wnt Signaling ◽

Canonical Wnt

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Mature enteroendocrine cells contribute to basal and pathological stem cell dynamics in the small intestine

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00036.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. G495-G510 ◽

Cited By ~ 14

Author(s):

Yoshitatsu Sei ◽

Jianying Feng ◽

Leigh Samsel ◽

Ayla White ◽

Xilin Zhao ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Intestinal Epithelium ◽

Lineage Tracing ◽

Enteroendocrine Cells ◽

Intestinal Stem Cells ◽

Intestinal Tumors ◽

Cell Dynamics ◽

Neutral Drift ◽

Rapid Generation

Lgr5-expressing intestinal stem cells (ISCs) maintain continuous and rapid generation of the intestinal epithelium. Here, we present evidence that dedifferentiation of committed enteroendocrine cells (EECs) contributes to maintenance of the epithelium under both basal conditions and in response to injury. Lineage-tracing studies identified a subset of EECs that reside at +4 position for more than 2 wk, most of which were BrdU-label-retaining cells. Under basal conditions, cells derived from these EECs grow from the bottom of the crypt to generate intestinal epithelium according to neutral drift kinetics that is consistent with dedifferentiation of mature EECs to ISCs. The lineage tracing of EECs demonstrated reserve stem cell properties in response to radiation-induced injury with the generation of reparative EEC-derived epithelial patches. Finally, the enterochromaffin (EC) cell was the predominant EEC type participating in these stem cell dynamics. These results provide novel insights into the +4 reserve ISC hypothesis, stem cell dynamics of the intestinal epithelium, and in the development of EC-derived small intestinal tumors. NEW & NOTEWORTHY The current manuscript demonstrating that a subset of mature enteroendocrine cells (EECs), predominantly enterochromaffin cells, dedifferentiates to fully functional intestinal stem cells (ISCs) is novel, timely, and important. These cells dedifferentiate to ISCs not only in response to injury but also under basal homeostatic conditions. These novel findings provide a mechanism in which a specified cell can dedifferentiate and contribute to normal tissue plasticity as well as the development of EEC-derived intestinal tumors under pathologic conditions.

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