Cyclosporin A Has Direct Effects on Adult Neural Precursor Cells

Abstract

Multipotent, self-renewing neural stem cells and their progeny [collectively referred to as neural precursor cells (NPCs)] represent a population of cells with great promise for CNS repair. To effectively harness their potential for therapeutic applications, the factors that regulate NPC behavior and/or fate must be well understood. The ability of immunomodulatory molecules to affect NPC behavior is of interest because of recent work elucidating the complex interactions between the immune system and nervous system. Herein, we examined the effects of cyclosporin A, a commonly used immunosuppressive molecule, on NPC proliferation kinetics, survival, and fate using in vitro assays at the population level and at the single-cell level. The use of pure populations of NPCs revealed a direct effect of cyclosporin A on cell survival, resulting in increased numbers and larger colonies, with no effect on proliferation kinetics. Cyclosporin A did not alter the differentiation profile of NPC colonies, indicating that it did not promote selective survival of a particular neural lineage. Additionally, we observed decreased cell-cell adhesions in developing cyclosporin A-treated NPC colonies. Consistent with the in vitro observations, in vivo administration of cyclosporin A to adult animals increased the numbers of NPCs within the neurogenic niche lining the lateral ventricles. Together, our findings establish that cyclosporin A has direct effects on NPCs both in vitro and in vivo, making it a promising candidate molecule for developing clinically relevant strategies to stimulate NPCs for brain repair.

Semi-quantitative analysis of the effects of cyclosporine on remyelination following gliotoxic injection in the brainstem

“…Consistent with in vitro observations, in vivo administration of CsA to adult animals increased the numbers of NPCs within neurogenic niches lining the lateral ventricles 27 .…”

Effects of Neural Progenitor Cells on Sensorimotor Recovery and Endogenous Repair Mechanisms After Photothrombotic Stroke

“…Reasons for the unchanged neurogenesis and dendritogenesis after cyclosporine treatment in our experiments compared to previously published studies might include the use of higher cyclosporine doses in these studies and that experiments were performed with healthy animals. 15,16 However, although both groups of the cell therapy experiments received immunosuppression, we cannot completely rule out that cyclosporine A might confound our results because we performed no experiment that contains all 3 groups, NPC-treated animals and placebo-treated animals with and without immunosuppression.…”

“…1,26 Recent research suggests that cyclosporine A affects neurogenesis and dendritic plasticity. 15,16,28 To address this issue, we performed experiments that compared animals treated with cyclosporine A with a daily dose of 10 mg/kg body weight and placebo. In these experiments, we found no significant differences between the 2 groups regarding functional recovery improvement, neurogenesis in the dentate gyrus, microglial activation, and dendritic regeneration.…”

Role of neural precursor cells in promoting repair following stroke

“…Inhibition of p53 promotes survival through downregulation of p53-upregulated modulator of apoptosis (PUMA) [100,102] . More recently it was found that cyclosporine A (CsA), a commonly used immunosuppressive drug, acts directly on NPCs to increase their survival without affecting cell cycle kinetics [103] . While the pro-survival mechanism has not been fully elucidated, the administration of CsA in vivo resulted in >2 fold increase in the size of the NPC pool in control mice.…”