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While specific projects may change over time, our dedication to the following research fields remains constant.

I: Develop culture platform to differentiate germ cells towards maturation with epigenetic remodeling for the purpose of disease modeling and mechanistic understanding
Image 4 iKS203 PGCLCs.jpg

The use of pluripotent stem cells for in vitro differentiation provides a most valuable approach to study human germ cell specification and to uncover genetic and epigenetic dysregulations associated with infertility. Our previous and recent work has demonstrated the establishment of formative pluripotency conditions for direct specification of primordial germ cell-like cells (PGCLCs) (Cheng Cell Reports 2019, Luo Cell Reports 2023). Building on this work, we plan to further develop in vitro differentiation platform using organoid co-culture to investigate the impact of genetic mutations on fertility. Specifically, our research has shown a focus on understanding the role of X-chromosome activity and mitochondrial dynamics in germ cell development.

II: Characterize the spatiotemporal regulation of germ cell migration and reveal the mechanisms of quality selection for gametogenesis

Germ cell migration is accompanied by extensive DNA demethylation and histone protein modification. We still know little about how these two sophisticated processes are coordinated. Furthermore, majority of migrating germ cells undergo apoptosis without further commitment to gametogenesis. We aim to use genetic mouse models, lineage tracing, single-cell sequencing among others to reveal gene function and mitochondrial dynamics during migration, epigenetic resetting, and meiosis entry. Especially, we are focusing on human genetic mutations implicated in infertility/subfertility.

III: Investigate the role of germline transmission in epigenetic inheritance of diseases


Women are born with a pool of primary follicles, some of which are periodically matured for fertilization. Throughout a woman's reproductive life, the number and quality of the remaining follicles gradually decline, leading to a decrease in fertility and an increased risk of reproductive disorders. Besides genetics, environmental factors can affect the health and function of the oocytes through dynamic interaction with niche cells. We are particularly interested in how maternal endocrine diseases such as polycystic ovarian syndrome (PCOS) and type I diabetes impact the transcriptome and metabolism of oocytes, which in turn affects their offspring's health across generations independent of uterine environmental effects. We are using diseased mouse models, IVF and surrogacy, and single-cell sequencing together with phenotyping and molecular assays.  

IV: Investigate the molecular basis of maternal-fetal communication in maternal endocrine diseases and their effects on offspring future health


We have previously showed that reproductive and metabolic traits of maternal PCOS can be transmitted across generations (Risal, Pei Nature Medicine 2019). To further delineate the role of adverse uterine environment versus germline transmission, we are carrying on several projects to study the role of the placenta in developmental programming and offspring’s future health. As increasing evidence has shown that the placenta is not functioned as a passive barrier, instead actively responds and adapts to uterine environment to impact fetal development. It is important to elucidate molecular adaptation of placentas in maternal endocrine diseases in function to maternal clinical features including hormone profiles. We also aim to mediate the placental function and prevent the developmental programming. To address these questions, mouse disease models, single-cell sequencing of human placentas as well placental organoids based chemical screening are applied to systematically examine molecular and phenotypic traits of mother, placentas and offspring and build molecular link underlying the developmental programming effects.

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