Mapping evolution of mammalian spermatogenesis via high resolution transcriptomics
FERTILITY AND STERILITY(2019)
摘要
Sperm are unique, highly specialized cells that carry genetic information from father to offspring and provide a continuous link between the past, present, and future of a species. In all mammals, the foundational unit of fertility is the spermatogonial stem cell (SSC), which must balance self-renewal with differentiation to ensure continuous sperm production. This is reliant on coordinated intrinsic (germ-cell mediated) and extrinsic (soma mediated) regulation to guide differentiation, commitment to meiosis, and morphological maturation. While decades of research in mice have provided a critical foundation of data, studies in primates have been limited to targeted subtypes based on a priori knowledge applied from rodents. However, fundamental differences exist between lineages, limiting the utility of mouse models. As a result, these processes are not well understood in humans and efforts to restore impaired spermatogenic function have had limited success. Here, we aim to identify key differences among species in these processes by conducting unbiased global evolutionary comparisons of expression between rodents and primates in the germline and soma throughout the course of spermatogenesis. Single cell RNA sequencing was performed on adult human and nonhuman primate testis, and datasets were analyzed both individually and also globally compared with our previously published mouse single cell atlas. Cryopreserved testes samples from 4 human and 5 macaque individuals were dissociated to single cell suspensions and isolated via microfluidics using the Drop-seq platform to conduct single-cell sequencing on multiple technical replicates. The data revealed a continuous developmental progression from spermatogonia to spermatids in adult humans (n=4, ∼14,000 cells) and rhesus macaques (n=5, ∼22,000 cells), thus capturing the complete germ cell differentiation process and analogous somatic cell types across all three species. Comparing pseudotime alignments of germ cell trajectories across species identified areas of similarity and dis-synchrony of germ cell maturation program, including differences in starting and ending states and a variable "clock rate” within the trajectories. Targeted analysis of spermatogonia computationally aligned discrete molecular states between species, revealing a unique undifferentiated population in primates, potentially containing SSCs. Characterization of underlying transcriptional programs and somatic cell inputs identified additional features of divergence. Our datasets provide new insights into differences in the intrinsic germ cell program and extrinsic signals required to promote germ cell differentiation in human, nonhuman primate, and rodent testes.
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关键词
mammalian spermatogenesis
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