BMP4 promotes human Sertoli cell proliferation via Smad1/5 and ID2/3 pathway and its abnormality is associated with azoospermia.

ABSTRACT

Sertoli cell plays critical roles in regulating testis development and spermatogenesis. Any change in the number or biological functions of Sertoli cells can affect the normal formation of spermatozoa. However, the roles and molecular mechanisms of factors in controlling the fate determinations of human Sertoli cells and underlying male infertility remain unknown. Here we have for the first time explored the function and signaling pathway of BMP4 in regulating adult human Sertoli cells and their association with non-obstructive azoospermia (NOA) patients. Immunocytochemistry and immunohistochemistry revealed that BMP4 and its multiple receptors were present in human Sertoli cells. Cell proliferation and BrdU incorporation assays showed that BMP4 promoted DNA synthesis and proliferation of Sertoli cells. In contrast, BMP4 antagonist noggin and BMP4 knockdown reduced the division of Sertoli cells. Moreover, BMP4 knockdown inhibited the synthesis of FGF2, SCF, zonula occludens 1, and claudin 11 but enhanced p27kip1 transcription. BMP4 activated Smad1/5 phosphorylation and upregulated ID2 and ID3 transcription, whereas noggin counteracted these increases. Significantly, tissue arrays disclosed that overexpression of BMP4 may be associated with Sertoli cell-only syndrome and maturation arrest in spermatogonia or spermatocytes. BMP4 was identified as the first autocrine factor that regulates the proliferation and protein synthesis of human Sertoli cells via Smad1/5 and ID2/3 and its abnormality is associated with human non-obstructive azoospermia patients. This study thus provides novel insights into molecular mechanism underlying adult human Sertoli cell growth and offers new targets for gene therapy of male infertility.