Cell atlas of the human female reproductive system across the lifespan

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Sexual reproduction depends on the fusion of gametes (sperm and eggs) during fertilisation followed by implantation of the resulting embryo in the lining of the womb (the endometrium). Gametes halve their genome in preparation for fertilisation during a specialized cell division known as meiosis. The process by which meiosis is co-ordinated with gamete formation in females is poorly understood, principally because it commences in utero and is not completed until decades later when the mature egg is ovulated and fertilised. From 3-5 weeks after fertilisation primordial germ cells (PGCs) begin to populate the ovary. Work on mice indicates that the PGCs form oogonia which undergo multiple rounds of mitotic cell division, remaining linked by cytoplasmic bridges as a consequence of incomplete cell division. Towards the end of the first trimester, these interlinked nests of cells begin to transition from mitosis to meiosis asynchronously across the ovary. The pre-meiotic round of DNA replication is followed by entry into meiotic prophase, which is marked by meiotic recombination following which pairs of homologous chromosomes remain linked at the sites of reciprocal exchange of DNA. This is co-ordinated with breakdown of cytoplasmic bridges to form individual oocytes, which in turn become surrounded by a small number of nurse cells (granulosa cells) to form a primordial follicle. Our knowledge of these events in the developing human ovary is fragmentary, and there appears be key differences between mouse and human. The pool of primordial follicles present at birth contain the life-time supply of oocytes. Little is known about how oocytes maintain cellular homeostasis during decades of arrest in the non-growing phase. Of particular interest are the mechanisms employed to maintain their nuclear and mitochondrial genomes in pristine condition for transmission to the next generation. Cohorts of primordial follicles are recruited from the pool on an ongoing basis. Initiation of oocyte growth is accompanied by morphological changes and reorganisation of the surrounding granulosa cells and it is not known whether this is a cause or a consequence of the initiation of oocyte growth, or indeed whether other surrounding cells, known as stromal cells, have a role in initiating oocyte growth. Following the onset of puberty, ovarian follicles can develop to the pro-ovulatory stage in response to hormonal triggers. Differentiation of the granulosa cells surrounding the oocyte enables fully grown oocytes to exit meiotic prophase and undergo the first meiotic division shortly before ovulation. In addition, hormones produced by the granulosa cells prepare the endometrium for implantation. While we have a broad understanding of the endocrine control of ovulation and endometrial priming, less is known about the molecular regulation of these transitions at the cellular level in the follicle and in the endometrium. To address the many gaps in our knowledge of the development of the female germline and reproductive system in humans, we propose to generate a comprehensive cell atlas of the human ovary and endometrium from fetal development until advanced reproductive age. We will combine gene-expression profiling at the single-cell level with new methods of gene-expression detection directly on the tissue to study the cellular environment at an unprecedented resolution and coverage. Information about the expression of the myriad of cells and cell states in the human ovary and endometrium will greatly advance our understanding of the development of the female reproductive system and the emergence and maintenance of the female germline in humans. The work will provide new insights into the causes of infertility and will inform strategies on how to grow oocytes in vitro.