TGFβ1 transduction enhances immunomodulatory capacity of neural stem cells in experimental autoimmune encephalomyelitis.

Bone marrow-derived neural stem cells (BM-NSCs) have therapeutic effect on EAE, an animal model of multiple sclerosis. However, the beneficial effect is suboptimal due to the limited immunomodulatory capacity of these cells. In this study, we engineered BM-NSCs with inducible TGFβ1, a potent immunosuppressive cytokine, to enhance their anti-inflammatory capacity. We found that i.v. injected TGFβ1-BM-NSCs more effectively suppressed clinical severity, inflammation and demyelination of the central nervous system of EAE mice. Transduction of TGFβ1 resulted in a higher percentage of Tregs and lower percentage of Th1 and Th17 cells in the periphery, with increased production of IL-10, and reduced production of IFN-γ, IL-17 and GM-CSF. Moreover, myelin-specific splenic proliferation was also inhibited more profoundly by TGFβ1-BM-NSCs. We also found that TGFβ1-BM-NSCs have the capacity to switch microglia from M1 to M2 phenotype. On the other hand, transduction of TGFβ1 did not affect proliferative ability and differentiating potential of BM-NSCs in vitro and in vivo. Together, these findings demonstrate that transduction of TGFβ1 significantly enhanced the immunomodulatory capacity of BM-NSCs for EAE treatment, through inducing Tregs and an M2 phenotype of macrophages/microglia, while retaining their capacity for neural cell differentiation. Thus, our study provides an easily accessible, inducible and effective therapy for CNS inflammatory demyelination.