The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells
Open Access
- 31 January 2011
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 208 (2), 285-294
- https://doi.org/10.1084/jem.20101559
Abstract
Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.Keywords
This publication has 42 references indexed in Scilit:
- Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in miceJCI Insight, 2010
- Protective Role of R-spondin1, an Intestinal Stem Cell Growth Factor, against Radiation-Induced Gastrointestinal Syndrome in MicePLOS ONE, 2009
- Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cellsNature Medicine, 2009
- R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/β-catenin pathwayProceedings of the National Academy of Sciences of the United States of America, 2009
- The intestinal stem cellGenes & Development, 2008
- Identification of stem cells in small intestine and colon by marker gene Lgr5Nature, 2007
- Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioningBlood, 2007
- R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6Proceedings of the National Academy of Sciences, 2007
- Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT)Blood, 2006
- Wnt signalling in stem cells and cancerNature, 2005