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CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation.

Jong Hoon Won1, Jacob S Choi1,2, Joon-Il Jun3

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The matricellular protein CCN1 regulates intestinal stem cell (ISC) balance by interacting with integrins. This interaction controls ISC self-renewal and differentiation, impacting nutrient absorption and overall intestinal homeostasis.

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Area of Science:

  • Cell Biology
  • Gastroenterology
  • Developmental Biology

Background:

  • Intestinal stem cells (ISCs) are crucial for maintaining intestinal homeostasis through a balance of self-renewal and differentiation.
  • The precise molecular mechanisms governing this critical ISC homeostatic balance are not fully understood.

Purpose of the Study:

  • To elucidate the role of the matricellular protein CCN1 in regulating intestinal stem cell proliferation and differentiation.
  • To identify the specific molecular pathways and interactions through which CCN1 exerts its control over ISC homeostasis.

Main Methods:

  • Utilized genetically modified mice with targeted deletion of Ccn1 in Lgr5+ ISCs or expression of integrin-binding deficient CCN1 mutants.
  • Employed intestinal crypt organoid cultures to analyze CCN1-mediated signaling pathways.
  • Investigated the involvement of integrins (αvβ3/αvβ5), NF-κB, Jag1, Notch, Src, YAP, and Wnt signaling.

Main Results:

  • Deletion of Ccn1 or its integrin-binding function in ISCs led to excessive ISC proliferation and skewed differentiation towards secretory cells, impairing nutrient absorption.
  • CCN1 interaction with integrins αvβ3/αvβ5 was shown to induce NF-κB-dependent Jag1 expression for Notch-mediated differentiation.
  • CCN1 also promoted Src-mediated YAP activation and Dkk1 expression, thereby regulating Wnt signaling for proliferation, with a positive feedback loop between CCN1 and YAP.

Conclusions:

  • CCN1 acts as a critical niche factor within the intestinal crypts, orchestrating ISC homeostasis.
  • CCN1 coordinates ISC self-renewal and differentiation through distinct integrin-dependent signaling pathways.
  • Matrix signaling, exemplified by CCN1, plays a pivotal role in the overarching control of intestinal stem cell fate and function.