Abstract
Prophylaxis for and treatment of graft-versus-host disease (GVHD) are essential for successful allogeneic hematopoietic stem cell transplantation (allo-SCT) and mainly consist of immunosuppressants such as calcineurin inhibitors. However, profound immunosuppression can lead to tumor relapse and infectious complications, which emphasizes the necessity of developing novel management strategies for GVHD. Emerging evidence has revealed that tissue-specific mechanisms maintaining tissue homeostasis and promoting tissue tolerance to combat GVHD are damaged after allo-SCT, resulting in exacerbation and treatment refractoriness of GVHD. In the gastrointestinal tract, epithelial regeneration derived from intestinal stem cells (ISCs), a microenvironment that maintains healthy gut microbiota, and physical and chemical mucosal barrier functions against pathogens are damaged by conditioning regimens and/or GVHD. The administration of growth factors for cells that maintain intestinal homeostasis, such as interleukin-22 (IL-22) for ISCs, R-spondin 1 (R-Spo1) for ISCs and Paneth cells, and interleukin-25 (IL-25) for goblet cells, mitigates murine GVHD. In this review, we summarize recent advances in the understanding of GVHD-induced tissue damage and emerging strategies for the management of GVHD.
Highlights
Mature epithelial cells in the gut, skin, and liver have long been recognized as the primary target of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation
The discovery of specific markers for tissue stem cells has enabled us to study the fate of tissue stem cells in mouse GVHD, and we found that intestinal stem cells (ISCs) and hair follicle stem cells (HFSCs) are targeted by GVHD
Niche components that support tissue stem cells are damaged after allo-SCT, likely inhibiting the recovery of tissue stem cells after GVHD-mediated injury
Summary
Mature epithelial cells in the gut, skin, and liver have long been recognized as the primary target of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT). Mature epithelial cells in the gut are composed of functionally distinct populations, including enterocytes, Paneth cells, goblet cells, tuft cells, and enteroendocrine cells. Each of these epithelial populations contributes to the maintenance of tissue homeostasis (Table 1). Injury of these epithelial cells results in alteration of the tissue microenvironment and disruption of tissue homeostasis, potentially amplifying GVHD-induced tissue damage. We review recent advances in the understanding the cellular and molecular mechanisms of GVHD-induced tissue damage and disruption of the tissue microenvironment
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