Wednesday, April 2, 2025
4/2/2025
Molecular mechanisms regulating formation of diverse stem cell progenitors - ABSTRACT/SUMMARY My group seeks to discover how regulated gene expression enables cells to choose distinct fates during embryogenesis. We focus on aspects of embryogenesis that are unique to mammals, such as extraembryonic tissues, because these bear the greatest lessons for human health and for stem cell biology. Using the mouse as a discovery platform, we aim to develop new models for understanding how extraembryonic tissues contribute to normal and pathological human development. Extraembryonic tissues include placenta, yolk sac, and umbilical cord. These are not created by the mother. Rather, they are among the first tissue types created by the embryo, very early in development, to allow ensuing gestation. For instance, within three days of fertilization, the mouse embryo sets aside extraembryonic endoderm cells, which are essential for normal development. At this, the blastocyst stage, extraembryonic endoderm and embryonic cells coexist within an inner cell mass. Notably, both cell types are also stem cell progenitors. The embryonic cells, also called epiblast, are pluripotent and are the progenitors of embryonic stem (ES) cells, while extraembryonic endoderm stem (XEN) cells can be derived from extraembryonic endoderm. The transcription factor OCT4 (POU5F1) has long been recognized as essential for pluripotency, epiblast, and ES cells. Additionally, OCT4 helps induce formation of ES-like cells called induced pluripotent stem (iPS) cells during somatic cell reprogramming. We discovered that, in addition to these pluripotency-inducing roles, OCT4 is also essential for extraembryonic endoderm and XEN cells. Moreover, we showed that OCT4 helps induce formation of XEN-like cells (iXEN cells) during reprogramming. Altogether, this evidence reveals that OCT4 possesses two distinct, but critical, cell type-specific roles: inducing pluripotency and extraembryonic endoderm fate in parallel. However, it is still unclear how OCT4 achieves these two distinct functions. Our approach is to integrate classical embryology approaches (e.g., knockouts, chimeras, imaging), stem cell models (e.g., in vivo and in vitro differentiation, reprogramming) with newly-developed tools for low-input genomics to produce time-resolved, single-cell, mechanistic knowledge of the targets of OCT4 in the gene regulatory network of extraembryonic endoderm in vivo, and to develop new models for the study of human extraembryonic endoderm in vitro.
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