BACKGROUND Mammalian reproduction requires the fusion of two specialized cells: an oocyte and a sperm. In addition to producing gametes, the reproductive system also provides the environment for the appropriate development of the embryo. Deciphering the reproductive system requires understanding the functions of each cell type and cell–cell interactions. Recent single-cell omics technologies have provided insights into the gene regulatory network in discrete cellular populations of both the male and female reproductive systems. However, these approaches cannot examine how the cellular states of the gametes or embryos are regulated through their interactions with neighboring somatic cells in the native tissue environment owing to tissue disassociations. Emerging spatial omics technologies address this challenge by preserving the spatial context of the cells to be profiled. These technologies hold the potential to revolutionize our understanding of mammalian reproduction. OBJECTIVE AND RATIONALE We aim to review the state-of-the-art spatial transcriptomics (ST) technologies with a focus on highlighting the novel biological insights that they have helped to reveal about the mammalian reproductive systems in the context of gametogenesis, embryogenesis, and reproductive pathologies. We also aim to discuss the current challenges of applying ST technologies in reproductive research and provide a sneak peek at what the field of spatial omics can offer for the reproduction community in the years to come. SEARCH METHODS The PubMed database was used in the search for peer-reviewed research articles and reviews using combinations of the following terms: ‘spatial omics’, ‘fertility’, ‘reproduction’, ‘gametogenesis’, ‘embryogenesis’, ‘reproductive cancer’, ‘spatial transcriptomics’, ‘spermatogenesis’, ‘ovary’, ‘uterus’, ‘cervix’, ‘testis’, and other keywords related to the subject area. All relevant publications until April 2023 were critically evaluated and discussed. OUTCOMES First, an overview of the ST technologies that have been applied to studying the reproductive systems was provided. The basic design principles and the advantages and limitations of these technologies were discussed and tabulated to serve as a guide for researchers to choose the best-suited technologies for their own research. Second, novel biological insights into mammalian reproduction, especially human reproduction revealed by ST analyses, were comprehensively reviewed. Three major themes were discussed. The first theme focuses on genes with non-random spatial expression patterns with specialized functions in multiple reproductive systems; The second theme centers around functionally interacting cell types which are often found to be spatially clustered in the reproductive tissues; and the thrid theme discusses pathological states in reproductive systems which are often associated with unique cellular microenvironments. Finally, current experimental and computational challenges of applying ST technologies to studying mammalian reproduction were highlighted, and potential solutions to tackle these challenges were provided. Future directions in the development of spatial omics technologies and how they will benefit the field of human reproduction were discussed, including the capture of cellular and tissue dynamics, multi-modal molecular profiling, and spatial characterization of gene perturbations. WIDER IMPLICATIONS Like single-cell technologies, spatial omics technologies hold tremendous potential for providing significant and novel insights into mammalian reproduction. Our review summarizes these novel biological insights that ST technologies have provided while shedding light on what is yet to come. Our review provides reproductive biologists and clinicians with a much-needed update on the state of art of ST technologies. It may also facilitate the adoption of cutting-edge spatial technologies in both basic and clinical reproductive research.

中文翻译：

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用空间转录组学解剖哺乳动物的繁殖


背景 哺乳动物的繁殖需要两个特殊细胞的融合：卵母细胞和精子。除了产生配子外，生殖系统还为胚胎的适当发育提供了环境。破译生殖系统需要了解每种细胞类型的功能和细胞间相互作用。最近的单细胞组学技术为雄性和雌性生殖系统的离散细胞群中的基因调控网络提供了见解。然而，由于组织解离，这些方法无法检查配子或胚胎的细胞状态如何通过与天然组织环境中相邻体细胞的相互作用来调节。新兴的空间组学技术通过保留待分析细胞的空间背景来应对这一挑战。这些技术有可能彻底改变我们对哺乳动物繁殖的理解。目标和基本原理 我们的目标是回顾最先进的空间转录组学 （ST） 技术，重点是突出它们在配子发生、胚胎发生和生殖病理学背景下帮助揭示的有关哺乳动物生殖系统的新生物学见解。我们还旨在讨论将 ST 技术应用于生殖研究的当前挑战，并先睹为快空间组学领域在未来几年可以为生殖界提供什么。 检索方法 PubMed 数据库用于使用以下术语的组合来检索同行评审的研究文章和评论：“空间组学”、“生育”、“生殖”、“配子发生”、“胚胎发生”、“生殖癌症”、“空间转录组学”、“精子发生”、“卵巢”、“子宫”、“子宫颈”、“睾丸”和与主题领域相关的其他关键字。截至 2023 年 4 月的所有相关出版物都经过了严格评估和讨论。结果 首先，概述了已应用于研究生殖系统的 ST 技术。讨论了这些技术的基本设计原则以及优点和局限性，并将其制成表格，以作为研究人员选择最适合自己研究的技术的指南。其次，全面回顾了对哺乳动物生殖的新生物学见解，尤其是 ST 分析揭示的人类生殖。讨论了三个主要主题。第一个主题侧重于在多个生殖系统中具有特殊功能的非随机空间表达模式的基因;第二个主题围绕功能相互作用的细胞类型，这些细胞类型通常被发现在空间上聚集在生殖组织中;第三个主题讨论了生殖系统的病理状态，这些状态通常与独特的细胞微环境有关。最后，强调了当前应用 ST 技术研究哺乳动物繁殖的实验和计算挑战，并提供了应对这些挑战的潜在解决方案。 讨论了空间组学技术发展的未来方向以及它们将如何使人类生殖领域受益，包括细胞和组织动力学的捕获、多模态分子分析和基因扰动的空间表征。更广泛的影响与单细胞技术一样，空间组学技术在为哺乳动物繁殖提供重要和新颖的见解方面具有巨大的潜力。我们的综述总结了 ST 技术提供的这些新颖的生物学见解，同时阐明了尚未发生的事情。我们的综述为生殖生物学家和临床医生提供了有关 ST 技术现状的急需更新。它还可能促进尖端空间技术在基础和临床生殖研究中采用。