Reconstitution of spermatogenesis and continuous generation of functional haploid germ cells in mouse testicular organoids

作者：Cong Wan, Qi Li, Zhaokai Yao, Z. Ye, Jiexiang Zhao, Shaofang Ren, Xingguo Xue, Kang Tang, Qi Rao, Yetian Weng, Hui Xu, Wen Wang, Chuxin Zhong, Xiaotian Li, Xinyan Yang, Minjia Pan, Manman Cui, Linzi Ma, Dingyao Chen, Chaohui Li, Ziye Zheng, Yi Zheng, Yang Liu, Gang Chang, Kai Miao, Fang Luo, Xiaoyang Zhao · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-71254-w · 被引用次数：3 · 研究领域：Sperm and Testicular Function、Pluripotent Stem Cells Research、Testicular diseases and treatments

Testicular organoids that support spermatogenesis and generate functional haploid germ cells are still lacking. Here, we developed a formation-differentiation culture approach to generate optimized testicular organoids (O-Torgs) derived from neonatal mouse primary testicular cells. These O-Torgs could essentially recapitulate the seminiferous tubule morphogenesis, Sertoli cell maturation, and testosterone secretion. Importantly, O-Torgs not only support spermatogenesis but also sustain proliferative undifferentiated spermatogonia and continuous generation of functional haploid cells for up to three months, with offspring derived from these haploid cells displaying normal growth and reproductive capability to the F2 generation. Mechanistically, we found that the formation stage enhanced the reconstruction of tubule-like structures and subsequent spermatogenesis by providing a more conducive extracellular matrix niche. Finally, O-Torgs were proven to be effective in modeling male infertility and drug screening, with BTT-3033 acting as a potential drug in protecting busulfan-mediated germ cell loss. Overall, our work establishes a strategy to obtain functional testicular organoids, offering promising avenues for male infertility modeling and drug discovery. Here, they develop optimized mouse testicular organoids that recapitulate key testicular functions and generate functional haploid germ cells, enabling the generation of normal fertile F2 offspring. These organoids can be use...