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单细胞RNA测序和单细胞染色质可及性测序表明，在非梗阻性无精子症中，支持细胞通过阶段特异性通讯介导精子发生障碍。

scRNA-seq and scATAC-seq reveal that Sertoli cell mediates spermatogenesis disorders through stage-specific communications in non-obstructive azoospermia.

作者信息

Wang Shimin, Wang Hongxian, Jin Bicheng, Yan Hongli, Zheng Qingliang, Zhao Dong

机构信息

Prenatal Diagnosis Center, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Department of Gynaecology and Obstetrics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

出版信息

Elife. 2025 May 15;13:RP97958. doi: 10.7554/eLife.97958.

DOI:10.7554/eLife.97958
PMID:40371706
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12081002/
Abstract

Non-obstructive azoospermia (NOA) belongs to male infertility due to spermatogenesis failure. However, evidence for cell type-specific abnormalities of spermatogenesis disorders in NOA remains lacking. We performed single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on testicular tissues from patients with obstructive azoospermia (OA) and NOA. HE staining confirmed the structural abnormalities of the seminiferous tubules in NOA patients. We identified 12 germ cell subtypes (spermatogonial stem cell-0 [SSC0], SSC1, SSC2, diffing-spermatogonia [Diffing-SPG], diffed-spermatogonia [Diffed-SPG], pre-leptotene [Pre-Lep], leptotene-zygotene [L-Z], pachytene [Pa], diplotene [Di], spermatids-1 [SPT1], SPT2, and SPT3) and 8 Sertoli cell subtypes (SC1-SC8). Among them, three novel Sertoli cell subtype phenotypes were identified, namely SC4/immature, SC7/mature, and SC8/further mature Sertoli cells. For each germ or Sertoli cell subtype, we identified unique new markers, among which immunofluorescence confirmed co-localization of ST3GAL4, A2M, ASB9, and TEX19 and DDX4 (classical marker of germ cell). PRAP1, BST2, and CCDC62 were co-expressed with SOX9 (classical marker of Sertoli cell) in testes tissues also confirmed by immunofluorescence. The interaction between germ cell subtypes and Sertoli cell subtypes exhibits stage-specific-matching pattern, as evidenced by SC1/2/5/7 involving in SSC0-2 development, SC3 participating in the whole process of spermiogenesis, SC4/6 participating in Diffing and Diffed-SPG development, and SC8 involving in the final stage of SPT3. This pattern of specific interactions between subtypes of germ cell and Sertoli cell was confirmed by immunofluorescence of novel markers in testes tissues. The interaction was mainly regulated by the Notch1/2/3 signaling. Our study profiled the single-cell transcriptome of human spermatogenesis and provided many potential molecular markers for developing testicular puncture-specific marker kits for NOA patients.

摘要

非梗阻性无精子症（NOA）属于因精子发生失败导致的男性不育症。然而，关于NOA中精子发生障碍的细胞类型特异性异常的证据仍然缺乏。我们对梗阻性无精子症（OA）和NOA患者的睾丸组织进行了单细胞RNA测序（scRNA-seq）和转座酶可及染色质测序的单细胞分析（scATAC-seq）。苏木精-伊红（HE）染色证实了NOA患者曲细精管的结构异常。我们鉴定出12种生殖细胞亚型（精原干细胞0 [SSC0]、SSC1、SSC2、分化型精原细胞[Diffing-SPG]、已分化精原细胞[Diffed-SPG]、前细线期[Pre-Lep]、细线期-偶线期[L-Z]、粗线期[Pa]、双线期[Di]、精子细胞1 [SPT1]、SPT2和SPT3）和8种支持细胞亚型（SC1-SC8）。其中，鉴定出三种新的支持细胞亚型表型，即SC4/未成熟型、SC7/成熟型和SC8/进一步成熟型支持细胞。对于每种生殖细胞或支持细胞亚型，我们鉴定出了独特的新标志物，其中免疫荧光证实了ST3GAL4、A2M、ASB9和TEX19与DDX4（生殖细胞的经典标志物）共定位。PRAP1、BST2和CCDC62也与SOX9（支持细胞的经典标志物）在睾丸组织中共表达，这也通过免疫荧光得到了证实。生殖细胞亚型与支持细胞亚型之间的相互作用呈现出阶段特异性匹配模式，如SC1/2/5/7参与SSC0-2的发育，SC3参与精子形成的全过程，SC4/6参与Diffing和Diffed-SPG的发育，SC8参与SPT3的最后阶段。生殖细胞和支持细胞亚型之间这种特异性相互作用模式通过睾丸组织中新标志物的免疫荧光得到了证实。这种相互作用主要受Notch1/2/3信号通路调控。我们的研究描绘了人类精子发生的单细胞转录组，并为开发针对NOA患者的睾丸穿刺特异性标志物试剂盒提供了许多潜在的分子标志物。

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