Kaltsas Aris, Kyrgiafini Maria-Anna, Markou Eleftheria, Koumenis Andreas, Mamuris Zissis, Dimitriadis Fotios, Zachariou Athanasios, Chrisofos Michael, Sofikitis Nikolaos
Third Department of Urology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece.
Laboratory of Genetics, Comparative and Evolutionary Biology, Department of Biochemistry and Biotechnology, University of Thessaly, Viopolis, Mezourlo, 41500 Larissa, Greece.
Int J Mol Sci. 2025 Jul 30;26(15):7383. doi: 10.3390/ijms26157383.
Male-factor infertility accounts for approxiamately half of all infertility cases globally, yet therapeutic options remain limited for individuals with no retrievable spermatozoa, such as those with non-obstructive azoospermia (NOA). In recent years, artificial gametogenesis has emerged as a promising avenue for fertility restoration, driven by advances in two complementary strategies: organotypic in vitro spermatogenesis (IVS), which aims to complete spermatogenesis ex vivo using native testicular tissue, and in vitro gametogenesis (IVG), which seeks to generate male gametes de novo from pluripotent or reprogrammed somatic stem cells. To evaluate the current landscape and future potential of these approaches, a narrative, semi-systematic literature search was conducted in PubMed and Scopus for the period January 2010 to February 2025. Additionally, landmark studies published prior to 2010 that contributed foundational knowledge in spermatogenesis and testicular tissue modeling were reviewed to provide historical context. This narrative review synthesizes multidisciplinary evidence from cell biology, tissue engineering, and translational medicine to benchmark IVS and IVG technologies against species-specific developmental milestones, ranging from rodent models to non-human primates and emerging human systems. Key challenges-such as the reconstitution of the blood-testis barrier, stage-specific endocrine signaling, and epigenetic reprogramming-are discussed alongside critical performance metrics of various platforms, including air-liquid interface slice cultures, three-dimensional organoids, microfluidic "testis-on-chip" devices, and stem cell-derived gametogenic protocols. Particular attention is given to clinical applicability in contexts such as NOA, oncofertility preservation in prepubertal patients, genetic syndromes, and reprocutive scenarios involving same-sex or unpartnered individuals. Safety, regulatory, and ethical considerations are critically appraised, and a translational framework is outlined that emphasizes biomimetic scaffold design, multi-omics-guided media optimization, and rigorous genomic and epigenomic quality control. While the generation of functionally mature sperm in vitro remains unachieved, converging progress in animal models and early human systems suggests that clinically revelant IVS and IVG applications are approaching feasibility, offering a paradigm shift in reproductive medicine.
男性因素导致的不孕症约占全球所有不孕症病例的一半,然而,对于那些无法获取精子的个体,如非梗阻性无精子症(NOA)患者,治疗选择仍然有限。近年来,人工配子发生作为一种恢复生育能力的有前景的途径出现了,这得益于两种互补策略的进展:器官型体外精子发生(IVS),旨在利用天然睾丸组织在体外完成精子发生;以及体外配子发生(IVG),试图从多能或重编程的体细胞干细胞中重新生成雄配子。为了评估这些方法的当前状况和未来潜力,我们在PubMed和Scopus上对2010年1月至2025年2月期间进行了叙述性、半系统性文献检索。此外,还回顾了2010年之前发表的具有里程碑意义的研究,这些研究为精子发生和睾丸组织建模提供了基础知识,以提供历史背景。这篇叙述性综述综合了细胞生物学、组织工程和转化医学的多学科证据,以根据从啮齿动物模型到非人类灵长类动物和新兴人类系统的物种特异性发育里程碑来衡量IVS和IVG技术。文中讨论了关键挑战,如血睾屏障的重建、阶段特异性内分泌信号传导和表观遗传重编程,同时还讨论了各种平台的关键性能指标,包括气液界面切片培养、三维类器官、微流控“芯片睾丸”装置和干细胞衍生的配子发生方案。特别关注了在NOA患者、青春期前患者的生育力保存、遗传综合征以及涉及同性或无伴侣个体的生殖场景等情况下的临床适用性。对安全性、监管和伦理考虑进行了严格评估,并概述了一个转化框架,该框架强调仿生支架设计、多组学指导的培养基优化以及严格的基因组和表观基因组质量控制。虽然体外产生功能成熟精子的目标尚未实现,但动物模型和早期人类系统的共同进展表明,与临床相关的IVS和IVG应用正接近可行性,这将给生殖医学带来范式转变。