Mesenchymal stem cells facilitate mixed hematopoietic chimerism induction and prevent onset of diabetes in nonobese diabetic mice.

Abstract

Allogeneic mesenchymal stem cells (MSCs) and bone marrow cells (BMCs) were cotransplanted in nonobese diabetic mice after none myeloablative preconditioning and the development of chimerism, insulitis, diabetes, and graft-versus-host disease (GVHD) were monitored. Eight-week-old female nonobese diabetic mice were injected intravenously with 2 × 10 BMCs and 5 × 10 MSCs from C57BL/6 mice after treatment with 2 intraperitoneal injections of anti-CD3 antibody (days -7 and -4) and 3-Gy total body irradiation (day -1). Thereafter, blood glucose and chimerism were monitored on peripheral blood samples. Stable mixed chimerism (3->90% of donor phenotype) was induced in 63.2% of BMCs-MSCs recipients (n = 19) and 45.0% of BMCs-alone recipients (n = 20, P = 0.256). Insulitis was prevented, and euglycemia persisted for more than 18 weeks in 89.5% of BMCs-MSCs recipients including those with less than 3% chimerism and 55% of BM-alone recipients (P < 0.05). In controls, 9.1% of mice receiving preconditioning treatment alone (n = 11) and 16.7% of preconditioned mice receiving only MSCs (n = 12) were nondiabetic. Graft-versus-host disease was not detected in all mice. Coinjection of MSCs and BMCs increased the success rate in inducing chimerism and preventing insulitis and overt diabetes with no incidence of GVHD. Results also indicated that even microchimerism with less than 3% donor cells is sufficient for blocking autoimmunity.