GUCY2C maintains intestinal LGR5+ stem cells by opposing ER stress

Authors

Crystal Kraft, Thomas Jefferson UniversityFollow
Jeff A. Rappaport, Thomas Jefferson UniversityFollow
Adam E. Snook, Thomas Jefferson UniversityFollow
Amanda M. Pattison, Thomas Jefferson UniversityFollow
John P. Lynch, University of Pennsylvania
Scott A. Waldman, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

10-26-2017

Comments

This article has been peer reviewed. It is the author’s final published version in Oncotarget

Volume 8, Issue 61, October 2017, Pages 102923-102933

The published version is available at DOI: 10.18632/oncotarget.22084. Copyright © Kraft et al.

Abstract

Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes to accommodate normal maintenance and post-injury regeneration of the epithelium. Their long life, lineage plasticity, and proliferative potential underlie the necessity for tight homeostatic regulation of the ISC compartment. In that context, the guanylate cyclase C (GUCY2C) receptor and its paracrine ligands regulate intestinal epithelial homeostasis, including proliferation, lineage commitment, and DNA damage repair. However, a role for this axis in maintaining ISCs remains unknown. Transgenic mice enabling analysis of ISCs (Lgr5-GFP) in the context of GUCY2C elimination (Gucy2c^-/-) were combined with immunodetection techniques and pharmacological treatments to define the role of the GUCY2C signaling axis in supporting ISCs. ISCs were reduced in Gucy2c^-/- mice, associated with loss of active Lgr5⁺ cells but a reciprocal increase in reserve Bmi1+ cells. GUCY2C was expressed in crypt base Lgr5+ cells in which it mediates canonical cyclic (c) GMPdependent signaling. Endoplasmic reticulum (ER) stress, typically absent from ISCs, was elevated throughout the crypt base in Gucy2c^-/- mice. The chemical chaperone tauroursodeoxycholic acid resolved this ER stress and restored the balance of ISCs, an effect mimicked by the GUCY2C effector 8Br-cGMP. Reduced ISCs in Gucy2c^-/-mice was associated with greater epithelial injury and impaired regeneration following sub-lethal doses of irradiation. These observations suggest that GUCY2C provides homeostatic signals that modulate ER stress and cell vulnerability as part of the machinery contributing to the integrity of ISCs. © Kraft et al.

Recommended Citation

Kraft, Crystal; Rappaport, Jeff A.; Snook, Adam E.; Pattison, Amanda M.; Lynch, John P.; and Waldman, Scott A., "GUCY2C maintains intestinal LGR5+ stem cells by opposing ER stress" (2017). Department of Pharmacology and Experimental Therapeutics Faculty Papers. Paper 90.
https://jdc.jefferson.edu/petfp/90

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This work is licensed under a Creative Commons Attribution 3.0 License.