Epithelial WNT2B and Desert Hedgehog Are Necessary for Human Colonoid Regeneration after Bacterial Cytotoxin Injury

Julie G In; Jianyi Yin; Roger Atanga; Michele Doucet; Robert N Cole; Lauren DeVine; Mark Donowitz; Nicholas C Zachos; Sarah E Blutt; Mary K Estes; Olga Kovbasnjuk

doi:10.1016/j.isci.2020.101618

Epithelial WNT2B and Desert Hedgehog Are Necessary for Human Colonoid Regeneration after Bacterial Cytotoxin Injury

iScience. 2020 Sep 28;23(10):101618. doi: 10.1016/j.isci.2020.101618. eCollection 2020 Oct 23.

Authors

Julie G In^{1

2}, Jianyi Yin², Roger Atanga¹, Michele Doucet², Robert N Cole³, Lauren DeVine³, Mark Donowitz², Nicholas C Zachos², Sarah E Blutt⁴, Mary K Estes^{4

5}, Olga Kovbasnjuk^{1

2}

Affiliations

¹ Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87131, USA.
² Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Biological Chemistry, Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

Intestinal regeneration and crypt hyperplasia after radiation or pathogen injury relies on Wnt signaling to stimulate stem cell proliferation. Mesenchymal Wnts are essential for homeostasis and regeneration in mice, but the role of epithelial Wnts remains largely uncharacterized. Using the enterohemorrhagic E. coli-secreted cytotoxin EspP to induce injury to human colonoids, we evaluated a simplified, epithelial regeneration model that lacks mesenchymal Wnts. Here, we demonstrate that epithelial-produced WNT2B is upregulated following injury and essential for regeneration. Hedgehog signaling, specifically activation via the ligand Desert Hedgehog (DHH), but not Indian or Sonic Hedgehog, is another driver of regeneration and modulates WNT2B expression. These findings highlight the importance of epithelial WNT2B and DHH in regulating human colonic regeneration after injury.

Keywords: Bacteriology; Bioengineering; Cell Biology; Tissue Engineering.

Abstract

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