Objective-Mesenchymal stem cells (MSCs) have been shown to possess immunomodulatory properties on a diverse array of immune cell lineages. However, their effect on B-lymphocytes has remained unclear. We investigated the effect of MSCs on B cell modulation with a special emphasis on gene regulation mediated by MSC humoral factors.Methods-MSCs were isolated from C57BL/6 bone marrow and expanded in culture. Splenic B cells were purified using anti-CD43 antibody and immunomagnetic beads. B cells and MSCs were co-cultured in separate compartments in a transwell system. For B cell stimulation, lipopolysaccharide (LPS) was used in vitro and T-dependent and T-independent antigens were used in vivo.Results-In MSC co-cultures, LPS-stimulated B cell proliferation was suppressed, CD138 + cell percentage decreased, and the number of apoptotic CD138 + cells decreased. In the B/MSC co-culture, the IgM + cell percentage was higher and the IgM amount released in the medium was lower than in the control. The Blimp-1 mRNA expression in the co-culture was suppressed throughout the 3 day culture period. Conditioned media derived from MSC cultures prevented the terminal differentiation of B cells in vitro and significantly suppressed the antigen specific IgM and IgG1 secretion in mice immunized with T cell-independent as well as T cell-dependent antigens in vivo. Conclusion-Resultsindicate that humoral factor(s) released by MSCs exert a suppressive effect on the B cell terminal differentiation. The suppression may be mediated through inhibition of Blimp-1 expression, but the nature of the factor(s) is yet to be determined.

Our results demonstrate the improvement of islet graft morphology and function by co-transplantation with MSCs. This improvement is attributable, at least in part, to the promotion of graft revascularization mediated by MSCs.

Background The activation of p38 mitogen-activated protein kinases (MAPK) is implicated in cold ischemia-reperfusion injury of donor organs. The islet isolation process, from pancreas procurement through islet collection, may activate p38MAPK leading to cytokine release and islet damage. This damage may be prevented by treating pancreata with a p38MAPK inhibitor (p38IH) prior to cold preservation. Methods Pancreata removed from Beagle dogs were infused with UW solution containing either the p38IH, SB203580 and Pefabloc (n=6) or vehicle (DMSO and Pefabloc) alone (n=7), through the pancreatic duct and preserved using the two-layer method. After 20–22 hours, islets were isolated and 3000 IEQ/kg were autotransplanted into the corresponding dog to monitor glucose metabolism. Results P38IH-treated pancreata yielded significantly more islets than control pancreata (IEQ/g: 2,134±297 vs. 1,477±145 IEQ/g or 65,012±9,385 vs. 45,700±5,103 IEQ/Pancreas; p<0.05). Apoptotic β-cell percentages assessed by LSC were lower in p38IH-treated than the controls (44±9.4% vs. 61.6±4.8%, p<0.05). TNF-α expression assessed by RT-PCR was significantly lower in the p38IH-treated group than controls. All dogs (3000 IEQ/kg) transplanted with p38IH-treated islets (n=5) became euglycemic vs. 4 of 5 dogs that received untreated islets. Plasma C-peptide levels following glucagon challenge were higher in animals receiving p38IH-treated islets (n=5) vs. untreated islets (n=4) (0.40±0.78 vs. 0.21±0.05 ng/mL, p<0.05). Conclusions Infusion of pancreata with UW solution containing p38IH through the duct prior to peservation suppresses cytokine release, prevents β cell apoptosis, and improves islet yield significantly with no adverse effect on islet function following transplantation. P38IH treatment of human pancreata may improve islet yield for use in clinical transplantation.

Induction of hematopoietic chimerism and subsequent donor-specific immune tolerance via bone marrow transplantation is an ideal approach for islet transplantation to treat type-1 diabetes. We examined the potential of mesenchymal stem cells (MSCs) in the induction of chimerism and islet allograft tolerance without the incidence of graft-versus-host disease (GVHD). Streptozotocin-diabetic rats received a conditioning regimen consisting of antilymphocyte serum and 5 Gy total body irradiation, followed by an intraportal co-infusion of allogeneic MSCs, bone marrow cells (BMCs) and islets. Although all the recipients rejected the islets initially, half of them developed stable mixed chimerism and donor-specific immune tolerance, shown by the engraftment of donor skin and second-set islet transplants and acute rejection of a third-party skin. The engraftment of the primary islet allografts with stable chimerism was achieved by the addition of a 2-week peritransplant administration of 15-deoxyspergualin (DSG). Without MSCs, none of the recipients treated with DSG developed chimerism or reversal of diabetes. GVHD was not observed in any of the recipients infused with MSCs (0/15), whereas it occurred in 4/11 recipients without MSCs. These results indicate a potential use of MSCs for induction of hematopoietic chimerism and subsequent immune tolerance in clinical islet transplantation.

Repeated Waon therapy improved right ventricular positive dP/dt, PH during exercise, exercise tolerance and the QOL in patients with severe COPD.