Abstract
SummaryThe 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.
Highlights
Human male puberty involves major changes in testis physiology, a large increase in testicular volume, and complex hormonal and molecular modulation, to accomplish both somatic cell proliferation/maturation and the initiation of spermatogenesis (Koskenniemi et al, 2017; Sharpe et al, 2003)
A tubular structure became progressively apparent in the 11-year-old sample, while a clear defined lamina and lumen were observed across the tubules of the 13- and 14-year-old samples (Figure 1B)
Single-Cell Profiling of Testes from T-Suppressed Transfemales previous data and our current analysis suggest a key role for AR and T in promoting testis development during puberty (Herbison, 2016; Koskenniemi et al, 2017), the molecular details involved are poorly characterized
Summary
Human male puberty involves major changes in testis physiology, a large increase in testicular volume, and complex hormonal and molecular modulation, to accomplish both somatic cell proliferation/maturation and the initiation of spermatogenesis (Koskenniemi et al, 2017; Sharpe et al, 2003). Puberty is initiated by re-activation of the hypothalamo-pituitary-gonadal axis following a period of relative quiescence during childhood (Plant, 2015) This hormonal control requires hypothalamic gonadotrophin-releasing hormone (GnRH) stimulating the release of gonadotrophins, luteinizing hormone (LH), and follicle stimulating hormone (FSH). Type B spermatogonia begin to develop at day 8 (d8) resulting in a synchronous ‘‘first wave’’ of spermatogenesis (Bellveet al., 1977), during which pro-spermatogonia undergo differentiation and synchronously generate both self-renewing and differentiating spermatogonia (Kluin and de Rooij, 1981; Yoshida et al, 2006). This results in the first round of murine sperm production at around d35 (Vergouwen et al, 1993). Humans lack the equivalent of this first wave of spermatogenesis and instead are believed to maintain spermatogonia in an undifferentiated (though largely uncharacterized) state prior to the initiation of puberty (Paniagua and Nistal, 1984)
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