Unveiling Leydig cell heterogeneity and its role in male infertility: A single-cell transcriptomic study of human testicular tissue

Male infertility and impaired spermatogenesis are significant concerns in reproductive health, often linked to disruptions in the cellular and molecular processes within the testis. The cellular composition and transcriptional dynamics of human testicular tissue are crucial for understanding these issues. Previous studies have largely relied on bulk tissue analysis, which obscures the distinct roles and interactions of specific cell types. Here, through a comprehensive single-cell transcriptomic analysis of human testes across various developmental stages and pathological conditions, we reveal the intricate cellular heterogeneity and the molecular mechanisms underlying testicular function. Our study identifies significant disruptions in the differentiation trajectories of Germ cells in conditions such as Klinefelter syndrome (KS), AZFa deletion, and Sertoli-cell-only syndrome (SCOS). We further uncover key transcription factors and regulatory networks governing Leydig cell function, particularly those related to steroidogenesis and hormonal regulation. These findings highlight the organized yet complex cellular and molecular landscape of the testis and uncover critical pathways altered in male infertility. Collectively, our data suggest that targeted therapeutic strategies could be developed to address specific disruptions in testicular cell populations and their associated regulatory networks.