Abstract
The fate of fetal germ cells (FGCs) in primordial follicles is largely determined by how they interact with the surrounding granulosa cells. However, the molecular mechanisms underlying this interactive process remain poorly understood. Here, we develop a computational model to characterize how individual genes program and rewire cellular crosstalk across FGCs and somas, how gene regulatory networks mediate signaling pathways that functionally link these two cell types, and how different FGCs diversify and evolve through cooperation and competition during embryo development. We analyze single-cell RNA-seq data of human female embryos using the new model, identifying previously uncharacterized mechanisms behind follicle development. The majority of genes (70%) promote FGC–soma synergism, only with a small portion (4%) that incur antagonism; hub genes function reciprocally between the FGC network and soma network; and germ cells tend to cooperate between different stages of development but compete in the same stage within a developmental embryo. Our network model could serve as a powerful tool to unravel the genomic signatures that mediate folliculogenesis from single-cell omics data.
Highlights
Primordial follicles of a female embryo, as women’s life-long fertility reserve, have been a longstanding focus of research in reproductive medicine [1,2,3]
Li et al.’s data [3] comprised 17 female embryos sampled at a range of developmental stages from 4 to 26 weeks post-fertilization, which formed an early stage of primordial folliculogenesis
By plotting the expression of each gene on each cell type against the niche index (NI) across embryos, we found that this relationship can be reasonably fitted by a power equation (p < 0.05; Figure S1), the form of curve fitting varied among genes and between cell type for the same gene (Figure 1)
Summary
Primordial follicles of a female embryo, as women’s life-long fertility reserve, have been a longstanding focus of research in reproductive medicine [1,2,3]. A primordial follicle consists of germ cells, surrounded by a single layer of flattened pregranulosa that supports germ cell growth. According to standard reproductive terminologies, germ cells from human female embryos before and after 11 weeks post-fertilization are called primordial germ cells and oogonia, respectively. Gonadal cells that surround FGCs are collectively referred to as somas. The past decade has witnessed the tremendous power of single-cell transcriptional and epigenetic data to monitor the developmental trajectories of FGCs and somas at unprecedented resolution [3,10,11]. One major reason is that it is difficult to map those complex omics data onto the spatiotemporal heterogeneity of follicle development
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