PDF(Pubmed)
Abstract：
Spermatogonial stem cell (SSC) acquisition of meiotogenetic state during puberty to produce genetically diverse gametes is blocked by drugs collectively referred as \'puberty blocker\' (PB). Investigating the impact of PB on juvenile SSC state and function is challenging due to limited tissue access and clinical data. Herein, we report largest clinically annotated juvenile testicular biorepository with all children with gender dysphoria on chronic PB treatment highlighting shift in pediatric patient demography in US. At the tissue level, we report mild-to-severe sex gland atrophy in PB treated children. We developed most extensive integrated single-cell RNA dataset to date (>100K single cells; 25 patients), merging both public and novel (52 month PB-treated) datasets, alongside innovative computational approach tailed for germ cells and evaluated the impact of PB and aging on SSC. We report novel constitutional ranges for each testicular cell type across the entire age spectrum, distinct effects of treatments on prepubertal vs adult SSC, presence of spermatogenic epithelial cells exhibiting post-meiotic-state, irrespective of age, puberty status, or PB treatment. Further, we defined distinct effects of PB and aging on testicular cell lineage composition, and SSC meiotogenetic state and function. Using single cell data from prepubertal and young adult, we were able to accurately predict sexual maturity based both on overall cell type proportions, as well as on gene expression patterns within each major cell type. Applying these models to a PB-treated patient that they appeared pre-pubertal across the entire tissue. This combined with the noted gland atrophy and abnormalities from the histology data raise a potential concern regarding the complete \'reversibility\' and reproductive fitness of SSC. The biorepository, data, and research approach presented in this study provide unique opportunity to explore the impact of PB on testicular reproductive health.
摘要：
精原干细胞（SSC）在青春期获得精原发育状态以产生遗传多样性配子，被统称为“青春期阻断剂”（PB）的药物阻断。研究PB对青少年SSC状态和功能的影响是具有挑战性的，因为组织访问和临床数据有限。在这里，我们报告了最大的经临床注释的幼年睾丸生物栓剂,所有儿童均患有慢性PB治疗的性别烦躁不安,突出了美国儿科患者人口统计学的转变.在组织层面,我们报道了PB治疗儿童的轻度至重度性腺萎缩.我们开发了迄今为止最广泛的整合单细胞RNA数据集（>100K单细胞；25名患者），合并公共和新颖(52个月PB处理)数据集，与创新的计算方法一起跟踪生殖细胞，并评估了PB和衰老对SSC的影响。我们报告了整个年龄范围内每种睾丸细胞类型的新构成范围，治疗对青春期前和成人SSC的不同影响，存在表现出减数分裂后状态的生精上皮细胞，不论年龄,青春期状态,或PB治疗。Further,我们定义了PB和衰老对睾丸细胞谱系组成的不同影响，SSC的代谢状态和功能。使用来自青春期前和年轻成年人的单细胞数据，我们能够根据整体细胞类型比例准确预测性成熟，以及每个主要细胞类型内的基因表达模式。将这些模型应用于PB治疗的患者，他们在整个组织中出现青春期前。这与组织学数据中注意到的腺体萎缩和异常相结合，引起了人们对SSC的完全“可逆性”和生殖适应性的潜在关注。生物储存库，数据,本研究提出的研究方法为探索PB对睾丸生殖健康的影响提供了独特的机会。
