Generation of human spermatogonia from pluripotent stem cells

Failures in germline development are a major cause of male infertility. However, the search for novel treatments is hampered by the lack of experimental systems that faithfully recapitulate human spermatogenesis. Here, we have developed a system to differentiate human induced pluripotent stem cells (iPSCs) into primordial germ cell-like cells that self-organize within xenogeneic reconstituted testes (xrTestes) generated from mouse fetal testicular cells. Subsequent transplant of xrTestes into immunodeficient mice resulted in efficient generation of undifferentiated and differentiated spermatogonia as well as preleptotene spermatocytes with striking similarities to their in vivo counterparts. As the fertilization competency of human iPSC-generated germ cells cannot be evaluated due to ethical constraints, we utilized a similar strategy to differentiate rhesus iPSCs through all fetal germ cell stages into spermatogonia-like cells. Together, these newly identified models of human gametogenesis will allow further mechanistic assessment of both germ cell development and genetic causes of infertility.