Teresa bridges two of the Institute鈥檚 research programmes, being jointly appointed to both the Epigenetics and Signalling programmes.
How do organisms keep track of time and what determines the lifespan of a species? The mechanisms that underlie biological timing remain largely unknown. Despite the high conservation of genetic programs throughout the animal kingdom, the duration of embryogenesis and lifespan are species-specific. For instance, mouse development lasts around 20 days, and the embryonic period of human gestation takes place during the first 60 days of pregnancy. This differences in timing arise at conception, as the progression from the fertilized zygote to embryo implantation lasts around four days in mouse whereas it takes seven days in human. Further, some species can halt development for extended periods of time (diapause) with no apparent trade-offs for development or lifespan.
Our lab studies the regulatory and dynamic processes that control timing in development and homeostasis across and within species with the long-term goal to modulate biological timing in a precise and tunable manner. Our current research questions are:
We make use of comparative human and mouse stem cell models as well as embryos to search for the regulatory mechanisms that determine species-specific timing. The lab employs genetic and pharmacological manipulations and quantitative and temporally resolved techniques such as flow cytometry, imaging, and genome-wide approaches to investigate the molecular and metabolic mechanisms that regulate developmental timing.
Overall, the identification of physiological mechanisms that modulate timing and its translation to stem cell models may have important implications in the field of human assisted reproduction, regenerative medicine, and aging. Changing the pace of developmental processes may facilitate the generation of clinically relevant cell types faster or it may allow lifespan extension.
Many mammals can temporally uncouple conception from parturition by pacing down their development around the blastocyst stage. In mice, this dormant state is achieved by decreasing the activity of the growth-regulating mTOR signaling pathway. It is unknown whether this ability is conserved in mammals in general and in humans in particular. Here, we show that decreasing the activity of the mTOR signaling pathway induces human pluripotent stem cells (hPSCs) and blastoids to enter a dormant state with limited proliferation, developmental progression, and capacity to attach to endometrial cells. These in聽vitro assays show that, similar to other species, the ability to enter dormancy is active in human cells around the blastocyst stage and is reversible at both functional and molecular levels. The pacing of human blastocyst development has potential implications for reproductive therapies.
Temporal control is central to deploy and coordinate genetic programs during development. At present, there is limited understanding of the molecular mechanisms that govern the duration and speed of developmental processes. Timing mechanisms may run in parallel and/or interact with each other to integrate temporal signals throughout the organism. In this piece, we consider findings on the extrinsic control of developmental tempo and discuss the intrinsic roles of cell cycle, metabolic rates, protein turnover, and post-transcriptional mechanisms in the regulation of tempo during neural development.
Mechanisms specifying amniotic ectoderm and surface ectoderm are unresolved in humans due to their close similarities in expression patterns and signal requirements. This lack of knowledge hinders the development of protocols to accurately model human embryogenesis. Here, we developed a human pluripotent stem cell model to investigate the divergence between amniotic and surface ectoderms. In the established culture system, cells differentiated into functional amnioblast-like cells. Single-cell RNA sequencing analyses of amnioblast differentiation revealed an intermediate cell state with enhanced surface ectoderm gene expression. Furthermore, when the differentiation started at the confluent condition, cells retained the expression profile of surface ectoderm. Collectively, we propose that human amniotic ectoderm and surface ectoderm are specified along a common nonneural ectoderm trajectory based on cell density. Our culture system also generated extraembryonic mesoderm-like cells from the primed pluripotent state. Together, this study provides an integrative understanding of the human nonneural ectoderm development and a model for embryonic and extraembryonic human development around gastrulation.