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. 2016 Aug 11;7(1):109.
doi: 10.1186/s13287-016-0376-2.

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

Kang Chao  1   2 , Shenghong Zhang  3 , Yun Qiu  1 , Xiaoyong Chen  4 , Xiaoran Zhang  4 , Chuang Cai  4 , Yanwen Peng  4 , Ren Mao  1 , Meirav Pevsner-Fischer  5 , Shomron Ben-Horin  1 , Eran Elinav  5 , Zhirong Zeng  1 , Baili Chen  1 , Yao He  1 , Andy Peng Xiang  6 , Minhu Chen  7
Affiliations

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

Kang Chao et al. Stem Cell Res Ther. .

Erratum in

Abstract

Background: 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.

Methods: The 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.

Results: HUC-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.

Conclusions: HUC-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.

Keywords: B regulatory cell; Colitis; Crohn’s disease; Mesenchymal stem cells; T helper cell.

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Figures

Fig. 1
Fig. 1
Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) therapy protects against TNBS-induced colitis. HUC-MSC therapy increased the survival rate of experimental colitis mice (a), decreased weight loss (b and c), alleviated colitis symptoms (d), and improved macroscopic (e) and histologic (f) scores. Myeloperoxidase (MPO) activity is shown in (g), and pictures of the colon (h) with hematoxylin and eosin staining (i) of each group are presented. The colon length which can reflect the inflammation was shown in (j). n = 20 for colitis model and treatment groups; n = 10 for model control and naïve mice; * P < 0.05 vs. MSC-treated mice. TNBS trinitrobenzenesulfonic acid
Fig. 2
Fig. 2
MSCs migrate to the inflamed areas. In vivo tracing of MSCs on days 1, 3, and 5, the labeled cells were detected by the imaging system. Warmer colors indicate more accumulation of cells. MSCs mesenchymal stem cells, TNBS trinitrobenzenesulfonic acid
Fig. 3
Fig. 3
hUC-MSCs alter numbers of regulatory T cells (Tregs) in colitis mice. Lymphocytes were co-stained with anti-CD4 and anti-FoxP3 antibodies and evaluated by flow cytometry. Tregs were defined as CD4+FoxP3+. The frequency of Tregs from the hUC-MSC-treated group was significantly lower than that in controls. Representative dot plots of Tregs in the spleen (a) and mesenteric lymph node (MLN) (c) of each group. Treg proportions are shown in (b) and (d). Data are presented as plots with P value. n = 9 for each group; * P < 0.05 vs. MSC-treated mice. hUC-MSC human umbilical cord-derived mesenchymal stem cell, TNBS trinitrobenzenesulfonic acid
Fig. 4
Fig. 4
hUC-MSCs alter T helper cell subgroups in colitis mice. Populations of Th1/Th2/Th17 cells as a proportion of total CD4+ cells were evaluated by flow cytometry. Cells were co-stained with antibodies against CD3, CD8, interferon (IFN)-γ, interleukin (IL)-4, or IL-17 (CD4+ cells). CD3+CD8- cells were gated (a). CD4+IFN-γ+, CD4+IL-4+, and CD4+IL-17+ cells were defined as Th1, Th2, and Th17 cells, respectively. Representative dot plots are shown in panels b–c. Proportions of Th1 and Th17 cells in the four participant groups are shown in panels d–g. Data are presented as plots with P value. n = 9 for each group; * P < 0.05 vs. MSC-treated mice. hUC-MSC human umbilical cord-derived mesenchymal stem cell, TNBS trinitrobenzenesulfonic acid
Fig. 5
Fig. 5
Serum cytokine expression in each group. Th1 cell-related cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-12) and Th17 cell-related cytokines (IL-6, IL-23, and IL-21) were decreased after cell transplantation. IL-10 and transforming growth factor (TGF)-β were increased after cell transplantation. For IL-17A, there was a decreased tendency (P = 0.09). n = 6 for each group; * P < 0.05 vs. TNBS-treated mice. hUC-MSC human umbilical cord-derived mesenchymal stem cell, TNBS trinitrobenzenesulfonic acid
Fig. 6
Fig. 6
CD5+ B cells significantly increase after hUC-MSC therapy. Populations of CD5+ B cells were identified as CD5+CD19+ by flow cytometry. Representative dot plots of CD5+ B cells in the spleen (a), mesenteric lymph node (MLN) (c), and peritoneal cavity (e) are shown. Data are presented as plots with P value (b, d and f). n = 9 for each group; * P < 0.05 vs. MSC-treated mice. hUC-MSC human umbilical cord-derived mesenchymal stem cell, TNBS trinitrobenzenesulfonic acid
Fig. 7
Fig. 7
Adaptive transfer of CD5+ B cells alleviates TNBS-induced colitis. Sorted CD5+ B cells (a) were used for transplantation. After adaptive transfer, the cells showed similar efficiency in colitis mice as hUC-MSCs (b–e), and this effect was associated with Treg/Th imbalances (f–i). hUC-MSC human umbilical cord-derived mesenchymal stem cell, MLN mesenteric lymph node, Th T helper, TNBS trinitrobenzenesulfonic acid
Fig. 8
Fig. 8
CD5+ B cells inhibit T-cell differentiation and are induced by hUC-MSCs. a–b CD5+ B cells inhibited carboxyfluorescein succinimidyl ester (CFSE)-labeled T cells. c–d CD5 + B cells express high level of interleukin (IL)-10, while CD5-B cells express significant lower level of IL-10 both in cell frequency and mRNA level. e–f CD5+ B cells were induced in vitro after co-culture with hUC-MSCs
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