Survival signal REG3α prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease

Dongchang Zhao, Yeung Hyen Kim, Seihwan Jeong, Joel K. Greenson, Mohammed S. Chaudhry, Matthias Hoepting, Erik R. Anderson, Marcel Rm van den Brink, Jonathan U. Peled, Antonio Lc Gomes, Ann E. Slingerland, Michael J. Donovan, Andrew C. Harris, John E. Levine, Umut Ozbek, Lora V Hooper, Thaddeus S. Stappenbeck, Aaron Ver Heul, Ta Chiang Liu, Pavan ReddyJames Lm Ferrara

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract remains the major cause of morbidity and nonrelapse mortality after BM transplantation (BMT). The Paneth cell protein regenerating islet-derived 3α (REG3α) is a biomarker specific for GI GVHD. REG3α serum levels rose in the systematic circulation as GVHD progressively destroyed Paneth cells and reduced GI epithelial barrier function. Paradoxically, GVHD suppressed intestinal REG3γ (the mouse homolog of human REG3α), and the absence of REG3γ in BMT recipients intensified GVHD but did not change the composition of the microbiome. IL-22 administration restored REG3γ production and prevented apoptosis of both intestinal stem cells (ISCs) and Paneth cells, but this protection was completely abrogated in Reg3g./. mice. In vitro, addition of REG3α reduced the apoptosis of colonic cell lines. Strategies that increase intestinal REG3α/γ to promote crypt regeneration may offer a novel, nonimmunosuppressive approach for GVHD and perhaps for other diseases involving the ISC niche, such as inflammatory bowel disease.

Original languageEnglish (US)
Pages (from-to)4970-4979
Number of pages10
JournalJournal of Clinical Investigation
Volume128
Issue number11
DOIs
StatePublished - Nov 1 2018

ASJC Scopus subject areas

  • Medicine(all)

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