Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells

Non -obstructive azoospermia (NOA) affects 1% of men. However, the unknowns of NOA pathogenesis and even normal spermatogenic microenvironment establishment severely limit the clinical efficacy of NOA treatment. We profiled > 80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. Sertoli cells, which form the scaffold in the testicular microenvironment, exhibited the most obvious damages in NOA patients. We identified roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature but with abnormal immune response, while the cells in idiopathic NOA (iNOA) are basically physiologically immature. Furthermore, inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective for the development of diagnostic methods and therapeutic targets for NOA. we profiled cells from 10 donors with normal spermatogenesis (one sample of 2, 5, 8, 11, 17 years old respectively and five normal adult samples) and 7 NOA patients (KS (3 cases), AZFa_Del (1 case), and iNOA (3 cases))