Human Mesenchymal Stem Cell-Treated Regulatory CD23⁺CD43⁺ B Cells Alleviate Intestinal Inflammation

Abstract

Rationale: Mesenchymal stem cells (MSCs) have been demonstrated to ameliorate inflammatory bowel disease by their actions on multiple immune cells, especially on regulatory B cells (Breg cells). However, the phenotypes and functions of human MSCs (hMSCs)-treated Breg cell subsets are not yet clear. Methods: Purified B cells were cocultured with MSCs and the phenotypes and immunomodulatory functions of the B cells were analyzed by FACS and proliferation assays in vitro . Also, a trinitrobenzenesulfonic acid-induced mouse colitis model was employed to detect the function of MSC-treated Breg cells in vivo . Results: We demonstrated that coculturing with hMSCs significantly enhanced the immunomodulatory activity of B cells by up-regulating IL-10 expression. We then identified that a novel regulatory B cell population characterized by CD23 and CD43 phenotypic markers could be induced by hMSCs. The CD23 + CD43 + Breg cells substantially inhibited the inflammatory cytokine secretion and proliferation of T cells through an IL-10-dependent pathway. More significantly, intraperitoneal injection of hMSCs ameliorated the clinical and histopathological severity in the mouse experimental colitis model, accompanied by an increase in the number of CD23 + CD43 + Breg cells. The adoptive transfer of CD23 + CD43 + B cells effectively alleviated murine colitis, as compared with the CD23 - CD43 - B cells. Treatment with CD23 + CD43 + B cells, and not hMSCs, substantially improved the symptoms of colitis in B cell-depleted mice. Conclusion: the novel CD23 + CD43 + Breg cell subset appears to be involved in the immunomodulatory function of hMSCs and sheds new light on elucidating the therapeutic mechanism of hMSCs for the treatment of inflammation-related diseases.

Immunomodulation of MSCs and MSC-Derived Extracellular Vesicles in Osteoarthritis

“…Chen et al found that MSCs can induce a new regulatory B-cell (Breg) population characterized by CD23 + CD43 + phenotypes. These CD23 + CD43 + Breg cells significantly inhibit the secretion of proinflammatory cytokines and the proliferation of T cells through the IL-10–dependent pathway (Carreras-Planella et al, 2019a ; Chen et al, 2019 ). Rafei et al found that MSCs inhibit the expression of transcription factor signal transducer and activator of transcription 3 (STAT3) via chemokine C-C motif chemokine ligand 2 (CCL2) and then induce paired box 5 (PAX5) protein synthesis to inhibit the secretion of immune globulin in plasma cells (Rafei et al, 2008 ) ( Figure 2 ).…”

The Immunomodulatory Effects of Mesenchymal Stem Cells on Regulatory B Cells

“…R Chen et al shown that PGE2 could induce B10 cells via the MAPKs/AKT-AP1 axis or aryl hydrocarbon receptor (AhR) signaling (108). Recently, COX-2/PGE2 pathway is also found to involved in MSCs induce CD23 + CD43 + Bregs, which significantly reducing the clinical and histopathological severity of induced colon inflammation and ameliorating gastrointestinal mucosal tissue damage in mice (59). However, IFN-γ-primed MSCs were reported to inhibit the production of IL-10 by LPS-activated B cells through the COX-2 pathway (83).…”

“…For instance, M. Franquesa et al experimentally demonstrated that hASCs can act independently of T cells and directly on B cells to promote the production of CD19 + CD24 high CD38 high and IL-10-production regulatory B cells ( 84 ). Although cell-to-cell contact manner have been confirmed to be involved in MSCs inducing Bregs by the transwell co-culture ( 59 , 80 ), little is known about the particular molecules. One of the major molecules involved in this cell-to-cell interaction of MSCs is the costimulatory molecules is programmed death ligand-1 (PD-L1, also known as B7-H1).…”

“…Summary of the studies on MSC-mediated effects to Bregs.Chen et al(76) Clinical trial: BOS after allo-HSCT Increased CD5 + B cells and IL-10-producing CD19 + CD5 + Bregs Chen et al(59) Colitis model Induced the novel CD23 + CD43 + Bregs subset Planella et al(77) Invitro study The PF as well as the CM could increase induced CD24 high CD38 high B cells…”

Extracellular vesicles derived from human placental mesenchymal stem cells alleviate experimental colitis in�mice by inhibiting inflammation and oxidative stress

“…Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic relapsing intestinal pathologies triggered by undefined etiological factors ( 1 , 2 ). The pathogenesis of IBD is complex, and no consensus theory is yet available to fully elucidate the development of IBD.…”