ProfessorPatrick Tam

Project Opportunities

Title: Control of cell differentiation during mouse embryogenesis and stem cell development

Summary of opportunity:

The research will provide insights into how progenitor cells for embryonic tissues may be specified and determine the conditions that promote differentiation into germ layer derivatives. The outcome will inform us on the molecular and signalling activities that control the first step of differentiation of multi-potent embryonic cells and stem cells to functionally competent cells.

Opportunity synopsis:

The knowledge of how to maintain, expand and differentiate stem cells is essential for the realisation of clinical cell-based therapy for the replacement and repair of diseased tissues.  Cells of the early embryo are capable of generating many cell types, hence are regarded as pluripotent cells.  As the embryo develops, there is a progressive restriction of the ability of the cells to do so.  Cells in more advanced embryos will give rise to an increasingly limited set of cell types.  We are documenting the genome-wide spatiotemporal multiomics of the cell population at all definable positions in the embryo, which will enable the tracking of the essential activity of the gene regulatory network and signalling pathways driving cell fate choices and lineage progression during gastrulation.  The network and pathway function will be verified by tracking lineage differentiation in genetically modified embryos and stem cell based embryo models.

Recently, stem cells have been derived from mouse embryos at the post-implantation stage.  These epiblast stem cells differ from the conventional embryonic stem cells, regarding the culture conditions for maintenance and differentiation, suggesting that they are a different type of stem cell that are already predisposed for more specialized differentiation.  This project will examine if these stem cells may be induced to differentiate more efficiently into specific types of embryonic tissue by recapitulating the genetic and signalling  activity that regulate cell differentiation in the embryo. Specifically, we will focus on one transcription factor, Mixl1, a cell-fate specifier expressed uniquely at this stage of development. We will study upstream signalling pathways (WNT,TGFb) that are controlling the expression of Mixl1 as well as its downstream targets. To this aim, stem cells will be differentiated by using cutting edge experimental tools such as gastruloid production and micro-patterning of cell populations that recapitulate the early embryo development. Transcriptome analysis of the cell population complemented with single cell analysis will be conducted to glean a comprehensive view of the molecular mechanisms of cell fate decision, which will inform us on how to generate by design of cell types with unique attributes for therapeutic application by design from other pluripotent stem cells.

----------Current Research Projects----------

Current research areas: 1. Developmental fate and lineage differentiation during embryogenesis 2. Gene regulatory network activity in head development 3. Transcriptional regulation and craniofacial development of normal and mutant embryos 4. Differentiation and organogenesis of endodermal tissues and the role of RNA binding protein 5. Developmental biology of embryo-derived stem cells and induced pluripotent stem cells