Cyclosporine A-Mediated IL-6 Expression Promotes Neural Induction in Pluripotent Stem Cells
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Differentiation of pluripotent stem cells (PSCs) to neural lineages has gathered huge attention in both basic research and regenerative medicine. The major hurdle lies in the efficiency of differentiation and identification of small molecules that facilitate neurogenesis would partly circumvent this limitation. The small molecule Cyclosporine A (CsA), a commonly used immunosuppressive drug, has been shown to enhance in vivo neurogenesis. To extend the information to in vitro neurogenesis, we examined the effect of CsA on neural differentiation of PSCs. We found CsA to increase the expression of neural progenitor genes during early neural differentiation. Gene silencing approach revealed CsA-mediated neural induction to be dependent on blocking the Ca2+-activated phosphatase calcineurin (Cn) signaling. Similar observation with FK506, an independent inhibitor of Cn, further strengthened the necessity of blocking Cn for enhanced neurogenesis. Surprisingly, mechanistic insight revealed Cn-inhibition dependent upregulation of IL-6 protein to be necessary for CsA-mediated neurogenesis. Together, these findings provide a comprehensive understanding of the role of CsA in neurogenesis, thus suggesting a method for obtaining large numbers of neural progenitors from PSCs for possible transplantation.
KeywordsNeural differentiation miPSCs Cyclosporine A Calcineurin-NFAT pathway FK506
Pluripotent stem cells
Induced pluripotent stem cells
Mouse induced pluripotent stem cells
Nuclear factor of activated T cells
Embryonic stem cells
Inactivated mouse embryonic fibroblasts
Leukemia inhibitory factor
We would like to thank AK lab members for critical review of all the data. We thank Prof. Catherine Verfaillie for the generous gift of Oct4-GFP iPSCs. This work was supported by grants from CSIR [no. 27(0294)/13/EMRII] and intramural funding from SORM, Manipal University.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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