Ciliary neurotrophic factor stimulates stem/progenitor Leydig cell proliferation but inhibits differentiation into its lineage in rats

Abstract Background Ciliary neurotrophic factor is a member of the interleukin‐6 family of cytokines. Ciliary neurotrophic factor drives many cells for their development. However, its effects on Leydig cell development remain unclear. Methods In the current study, we used three‐dimensional seminiferous tubule culture system to induce the proliferation and differentiation of tubule‐associated stem Leydig cells and primary progenitor Leydig cells culture to address the effects of ciliary neurotrophic factor. Results We found that ciliary neurotrophic factor stimulated the proliferation of stem Leydig cells but inhibited their development into the Leydig cell lineage. The ciliary neurotrophic factor‐mediated effects can be reversed by signal transducer and activator 3 inhibitor S3I‐201 and phosphatidylinositol 3‐kinase inhibitor wortmannin, indicating that ciliary neurotrophic factor acts via signal transducer and activator 3–phosphatidylinositol 3‐kinase signaling pathways to increase stem/progenitor Leydig cell proliferation. Ciliary neurotrophic factor at 1 and 10 ng/mL significantly decreased androgen production by progenitor Leydig cells. Microarray analysis of ciliary neurotrophic factor‐treated progenitor Leydig cells showed that ciliary neurotrophic factor blocked steroidogenic pathways by downregulating Scarb1 , Star , and Hsd3b1 , possibly by downregulating the transcription factor Nr5a1 expression. Conclusion Ciliary neurotrophic factor stimulates proliferation but blocks the differentiation of stem/progenitor Leydig cells.