Early switch in mammalian life
During early mammalian development, cells gradually lose totipotency, which is the ability to develop into all cell lineages. At around the 16-cell stage, blastomeres differentiate to create the first two cell lineages. The outer cells of the embryo adopt an epithelial cell fate and develop into the trophectoderm (TE) and the inner cells adopt an epiblast cell fate and create into the inner cell mass (ICM). The ICM and the in-vitro derivatives thereof, embryonic stem cells (ESCs), exhibit pluripotency and can thus give rise to all cell types of the adult organism. Cells that give rise to only one cell type exhibit unipotency. ICM cells eventually differentiate into all three embryonic germ layers and produce germ cells or gametes. Haploid germ cells are spermatozoa in the male and oocytes in the female. These specialized unipotent cells fuse together to form the totipotent zygote, thereby transmitting genetic information from parent to offspring.
Oct4 is a key gene in pluripotency
A pluripotent cell population is marked by the expression of the transcription factors Oct4, Nanog, and Sox2. Oct4 expression is downregulated in the TE yet maintained in the pluripotent ICM. During embryonic development, Oct4 expression becomes restricted to the epiblast and eventually silenced in differentiated, somatic cells. After gastrulation, Oct4 expression becomes restricted to unipotent primordial germ cells (PGCs), the precursors of gametes. Oct4 is instrumental in the establishment and maintenance of cellular pluripotency.
Some of our scientific questions
A paramount aim of my laboratory is the identification of further factors involved in pluripotency establishment and maintenance during embryonic development. Questions we address include:
- How do somatic cells differ from pluripotent cells and germ cells?
- Do specific components of the microenvironment of the ICM support the ICM’s proliferation and pluripotent phenotype?
- How is differential gene regulation established in pluripotent cells?
Our scientific goals
A deeper understanding of the molecular mechanisms underlying differences in differential gene regulation among these cells is crucial in elucidating their distinguishing features. We investigate epigenetic modifications in the transcriptional regulation of gene expression. We also identify factors involved in the re-establishment of pluripotency from the differentiated, somatic cell state, in an epigenetic conversion process called reprogramming. Finally, we examine how genetic manipulation of somatic cells with over-expression of different combinations/fewer factors may impact the efficiency and duration of reprogramming, in comparison with other established methods of reprogramming, such as somatic cell nuclear transfer.
Another goal of the department is the use of pluripotent stem cells to effectively model human diseases, which may not be fully recapitulated in animal models. The use of pluripotent stem cells holds tremendous biological relevance, allowing us to generate a virtually unlimited supply of specialized cells for in-vitro modeling of many types of disease afflicting humans. The ultimate goals of this research are to support detailed studies into the underlying mechanisms of human pathophysiologies and discover drugs with higher efficacy.