Human umbilical cord-derived mesenchymal stem cells protect against experimental colitis via CD5(+) B regulatory cells.

Kang Chao,Xiaoran Zhang,Ren Mao,Zhirong Zeng,Andy Peng Xiang,Shenghong Zhang,Chuang Cai,Yun Qiu,Meirav Pevsner-Fischer,Shomron Ben-Horin,Yanwen Peng,Minhu Chen,Baili Chen,Xiaoyong Chen,Yao He,Eran Elinav

doi:10.1186/s13287-016-0376-2

Abstract

BackgroundTo clarify the effect of human umbilical cord-derived mesenchymal stem cell (hUC-MSCs) treatment on colitis and to explore the role of CD5+ B cells in MSC therapy.MethodsThe trinitrobenzenesulfonic acid (TNBS)-induced colitis mouse model was used. HUC-MSCs were transferred peritoneally. Survival rates, colitis symptoms, and macroscopic and histologic scores were evaluated. CD4+ T helper (Th) cell subgroups and CD5+ regulatory B cell (Bregs) in lymphocytes were quantitated by flow cytometry. Cytokine levels were detected by ELISA and Bio-plex. CD5+ B cells were isolated for in vitro co-culture and adaptive transfer.ResultsHUC-MSC treatment alleviated TNBS-induced colitis by increasing survival rates, relieving symptoms, and improving macroscopic and histologic scores. Labeled hUC-MSCs were located in the inflamed areas of colitis mice. Increases in regulatory T cells (Tregs) and CD5+ B cells and decreases in Th1 cells, Th17 cells, and several pro-inflammatory cytokines were observed with hUC-MSC treatment. After adaptive transfer, CD5+ B cells, which were located mainly in the peritoneal lavage fluid, improved TNBS-induced colitis by correcting Treg/Th1/Th17 imbalances. CD5+ B cells also inhibited T-cell proliferation and produced interleukin (IL)-10.ConclusionsHUC-MSCs protected against experimental colitis by boosting the numbers of CD5+ B cells and IL-10-producing CD5+ Bregs, and correcting Treg/Th17/Th1 imbalances.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0376-2) contains supplementary material, which is available to authorized users.

Highlights

To clarify the effect of human umbilical cord-derived mesenchymal stem cell treatment on colitis and to explore the role of CD5+ B cells in Mesenchymal stem cells (MSCs) therapy
HUC-MSCs may migrate to the inflamed areas By in vivo cell tracing, we found that hUC-MSCs accumulated in the peritoneal cavity of trinitrobenzenesulfonic acid (TNBS) and ethanol mice on day 1 (6 hours after colitis induction), whereas only a few cells that were limited to the site of cell injection could be found in naïve mice
CD5+ B cells alleviated colitis in mice in vivo by regulating T-cell responses We found a significant increase in CD5+ B cells after cell transplantation in both splenic and mesenteric lymph node (MLN) lymphocytes (Fig. 6), suggesting that CD5+ B cells might play a role in immune regulation

Summary

Introduction

To clarify the effect of human umbilical cord-derived mesenchymal stem cell (hUC-MSCs) treatment on colitis and to explore the role of CD5+ B cells in MSC therapy. Crohn’s disease (CD) is a chronic, recurrent inflammatory disease of the gastrointestinal tract and is characterized by T-cell dysfunction, altered cytokine production, and cellular inflammation. These factors lead to mucosal damage of the alimentary tract. Many case series and pilot clinical trials have demonstrated the efficacy of stem cell therapy, but with much uncertainty [3]. Due to difficulties in obtaining sufficient autologous BM-MSCs, human MSCs obtained from the umbilical cord (hUC-MSCs) have recently emerged as an attractive alternative for cell therapy. In addition to its “immune-privileged” status and immunomodulatory properties, hUC-MSCs are easier to collect and expand in vitro [10, 11], making it a potentially promising tool in clinical applications

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