The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To ...characterize this understudied process, we profiled and analyzed single-cell transcriptomes of ∼10,000 testicular cells from four boys spanning puberty and compared them to those of infants and adults. During puberty, undifferentiated spermatogonia sequentially expand and differentiate prior to the initiation of gametogenesis. Notably, we identify a common pre-pubertal progenitor for Leydig and myoid cells and delineate candidate factors controlling pubertal differentiation. Furthermore, pre-pubertal Sertoli cells exhibit two distinct transcriptional states differing in metabolic profiles before converging to an alternative single mature population during puberty. Roles for testosterone in Sertoli cell maturation, antimicrobial peptide secretion, and spermatogonial differentiation are further highlighted through single-cell analysis of testosterone-suppressed transfemale testes. Taken together, our transcriptional atlas of the developing human testis provides multiple insights into developmental changes and key factors accompanying male puberty.
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•A transcriptional single-cell atlas of the developing testes during human puberty•Distinctive phases of germ cell differentiation occur during puberty•Identification of a common progenitor for Leydig and myoid cells prior to puberty•Partial reversal of Sertoli and germ cell maturation upon testosterone suppression
Guo et al. provide a transcriptional cell atlas of the developing human testis during puberty, revealing dramatic developmental changes in both germ and somatic niche cell lineages. Furthermore, germ cells and Sertoli cells from testosterone-suppressed transfemale testes display partial developmental reversal, revealing critical roles for testosterone in maintaining testis maturation.
Human testis development in prenatal life involves complex changes in germline and somatic cell identity. To better understand, we profiled and analyzed ∼32,500 single-cell transcriptomes of ...testicular cells from embryonic, fetal, and infant stages. Our data show that at 6–7 weeks postfertilization, as the testicular cords are established, the Sertoli and interstitial cells originate from a common heterogeneous progenitor pool, which then resolves into fetal Sertoli cells (expressing tube-forming genes) or interstitial cells (including Leydig-lineage cells expressing steroidogenesis genes). Almost 10 weeks later, beginning at 14–16 weeks postfertilization, the male primordial germ cells exit mitosis, downregulate pluripotent transcription factors, and transition into cells that strongly resemble the state 0 spermatogonia originally defined in the infant and adult testes. Therefore, we called these fetal spermatogonia “state f0.” Overall, we reveal multiple insights into the coordinated and temporal development of the embryonic, fetal, and postnatal male germline together with the somatic niche.
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•A transcriptional single-cell atlas of the fetal and postnatal human testes•Somatic niche cell types derive from a common progenitor ∼7 weeks after fertilization•PGCs transition directly into fetal state 0-like cells (state f0) starting at week 14•Fetal somatic niche cell specification precedes the PGC-to-state f0 transition
Guo et al. provide a transcriptional cell atlas of the fetal and postnatal human testes. Remarkably, starting from ∼14 weeks postfertilization, fetal primordial germ cells transition to a cell state highly similar to postnatal spermatogonial stem cells. Furthermore, somatic niche specification precedes this transition, which is consistent with guiding fetal germline development.
Aging men display reduced reproductive health; however, testis aging is poorly understood at the molecular and genomic levels. Here, we utilized single-cell RNA-seq to profile over 44,000 cells from ...both young and older men and examined age-related changes in germline development and in the testicular somatic cells. Age-related changes in spermatogonial stem cells appeared modest, whereas age-related dysregulation of spermatogenesis and somatic cells ranged from moderate to severe. Altered pathways included signaling and inflammation in multiple cell types, metabolic signaling in Sertoli cells, hedgehog signaling and testosterone production in Leydig cells, cell death and growth in testicular peritubular cells, and possible developmental regression in both Leydig and peritubular cells. Remarkably, the extent of dysregulation correlated with body mass index in older but not in younger men. Collectively, we reveal candidate molecular mechanisms underlying the complex testicular changes conferred by aging and their possible exacerbation by concurrent chronic conditions such as obesity.
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•A transcriptional single-cell atlas of testes from older men•Age-related changes in SSCs are modest•Age-related dysregulation of spermatogenesis and somatic cells are pronounced•Dysregulation correlated with BMI in older but not younger men
Guo, Cairns, and colleagues revealed aging-related alternations of human germ cells and testicular somatic cells through single-cell transcriptomic profiling, providing candidate molecular mechanisms underlying the complex testicular changes conferred by aging and their possible exacerbation by concurrent chronic conditions such as obesity.
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