The making of an ovarian niche

doi:10.1126/science.abj8347

GSTDTAP > 气候变化

DOI	10.1126/science.abj8347
	The making of an ovarian niche
	Lin Yang; Huck-Hui Ng
	2021-07-16
发表期刊	Science
出版年	2021
英文摘要	Nudging germ cell precursors into functionally mature oocytes and spermatozoa is a key aspect of in vitro gametogenesis and a major challenge in the study of reproductive biology. This process is biologically complex, not only determined by the developmental competency of the germ cell itself but also critically dependent on the gonadal niche. On page 298 of this issue, Yoshino et al. ([ 1 ][1]) report the in vitro derivation of fetal ovarian somatic cell–like cells (FOSLCs) from murine pluripotent embryonic stem cells, using a stepwise, directed differentiation strategy to reconstruct in vivo differentiation. These cells sufficiently supported the development of germ cell precursors into functional oocytes that went on to produce viable, fertile mice. The ability to generate and assemble the critical components necessary for oogenesis in the laboratory provides a model system to study the later events of oogenesis, and this may have implications for assisted reproductive technologies. The preceding decade saw great strides made in understanding early developmental processes in gametogenesis. In the laboratory, methods to direct the specialization of pluripotent stem cells—a renewable cell source—to primordial germ cell–like cells (PGCLCs) were established, first with mouse cells and eventually with human cells. ([ 2 ][2]–[ 4 ][3]). These were successful first steps toward recapitulating gametogenesis in vitro and producing functional germ cells entirely ex vivo. Further development of mammalian primordial germ cells occurs with their migration to the genital ridges (the location where gonads develop in both sexes) ([ 5 ][4]). In mammalian females, the developing oocyte is enveloped by ovarian somatic cells (in particular, the granulosa cells) that arise from the fetal gonads. The oocyte releases paracrine growth factors that instruct these support cells to provide nutrients to feed its growing metabolic needs ([ 6 ][5]). This connection is crucial for many developmental milestones, such as the phases of ovarian follicle formation and oocyte entry into meiosis. Mouse pluripotent stem cells have competency to spontaneously differentiate into follicle-like structures around an oocyte-like cell, but this occurs at very low efficiency ([ 7 ][6], [ 8 ][7]). Without a reliable in vitro source of the support cells, biologists have relied on either transplanting induced PGCLCs back to gonads in vivo or coculturing PGCLCs with dissociated mouse gonad somatic cells to derive functional oocytes ([ 9 ][8]–[ 11 ][9]). Either case requires a preparation procedure that has built-in variability and low scalability, is incompatible with the development of human cell–based systems, and is challenging to manipulate for basic research purposes. The approach of Yoshino et al. relied on using several morphogens [WNT (wingless-related integration site), BMP (bone morphogenetic protein), SHH (sonic hedgehog), and RA (retinoic acid)] to stimulate signaling pathways that guide the differentiation of mouse pluripotent cells (see the figure). Specifically, pluripotent stem cells were coaxed through a differentiation trajectory toward a region of the mesoderm (specifically, the anterior ventral intermediate mesoderm) where the gonads originate. Indeed, the resultant cells captured the cell identities and diversities of the fetal ovaries. Granulosa- and stromal-like cells, as well as less mature precursors, were generated, with transcriptomic signatures (profiles of gene expression) that closely resembled their in vivo counterparts. When FOSLCs were cultured in combination with mouse PGCLCs in three-dimensional aggregates, the “reconstituted ovarioids” supported follicle formation. The authors then achieved the gold standard of in vitro oogenesis—the derivation of healthy, fertile offspring after in vitro oocyte fertilization and transplantation of the embryo into a female mouse. This technical breakthrough of Yoshino et al. holds enormous potential for germ cell research. It allows for fully defined derivation of FOSLCs with substantial improvements in yield and without the need for genetic manipulations. The method will need further refinement—after all, a full recapitulation of all aspects of oogenesis in vitro is still challenging and complex. FOSLCs are less efficient than mouse gonadal somatic cells in generating healthy oocytes, possibly owing to lower proportions of granulosa-like cells among FOSLCs. In addition, it is not yet known how the cytoplasmic contents, or the genetic and epigenetic profiles of in vitro–derived oocytes, match up to those produced in vivo. Nonetheless, FOSLCs and reconstituted ovarioids allow the perturbation of individual molecular factors (for example, specific genes that regulate oogenesis), the investigation of cell type–specific roles of the niche in promoting oocyte maturation, and perhaps the application of bioengineering concepts, much like what has been attempted in tissue and organoid engineering fields, to create more physiological reconstituted ovarioids with higher efficiencies for oogenesis ([ 12 ][10]). ![Figure][11] Generation of follicles for in vitro oogenesis Mouse embryonic stem cells undergo stepwise differentiation into anterior ventral intermediate mesoderm, which gives rise to fetal ovaries. Resulting fetal ovarian somatic cell–like cells are cocultured with primordial germ cell–like cells, which support maturation into oocytes. These are competent to produce live, fertile offspring. GRAPHIC: N. DESAI/ SCIENCE What does this work mean for assisted reproductive technologies in humans, and how far away is the production of autologous, in vitro–derived gametes for clinical use? The proof-of-concept study from Yoshino et al. has made clear strides toward enabling in vitro gametogenesis at scale. Similar methods to obtain cells akin to human ovarian somatic cells will no doubt be attempted, but it remains to be seen how transferrable this strategy would be. After all, human gametogenesis occurs on a much lengthier time scale and likely places different requirements on both the germ cells and the supporting niche. For example, primordial germ cell development in humans diverges from that of the mouse in key aspects ([ 3 ][12]). It would be instructive to determine if molecular hallmarks of human oogenesis can be observed in reconstituted ovarioids consisting of human PGCLCs cultured with murine FOSLCs. Additionally, deriving functional gametes in vitro remains inefficient, even in the well-studied mouse model. The technical challenges for obtaining high-quality cells in humans are thus considerable. Efforts to overcome them will inevitably also come up against ethical conflicts, especially when the developmental competency of later-stage gametes needs to be ascertained. Molecular milestones for oocyte development will have to be used as much as possible, and nonhuman primate models will be particularly useful for demonstrating the final functionality of in vitro–derived gametes in an equivalent nonhuman primate system ([ 13 ][13]–[ 15 ][14]). Such studies will define the contours of the ethical discourse that the scientific community must carefully undertake with the public before any clinical application can be considered and eventually actualized. 1. [↵][15]1. T. Yoshino et al ., Science 373, eabe0237 (2021). [OpenUrl][16][Abstract/FREE Full Text][17] 2. [↵][18]1. K. Hayashi, 2. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计	被引频次：4[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334359
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Lin Yang,Huck-Hui Ng. The making of an ovarian niche[J]. Science,2021.
APA	Lin Yang,&Huck-Hui Ng.(2021).The making of an ovarian niche.Science.
MLA	Lin Yang,et al."The making of an ovarian niche".Science (2021).