Yan-Fung Wong｜ Institute of Cellular and Organismic Biology, Academia Sinica

Cell proliferation is crucial during embryonic development, especially for the expansion of endodermal progenitors that form organ primordia. Human pluripotent stem cells (hPSCs) can differentiate into all embryonic germ layers, including endoderm. However, the differentiated cells often remain immature, which restricts their potential for investigating early human organ formation and limits their practical usage. Introducing proliferation phases within progenitors during differentiation promotes cell stabilization and enhances maturation. 

Our lab has advanced this approach by expanding various stem cell progenitor populations derived from differentiating hPSCs, such as human ventral foregut (hVFG) stem cells. We demonstrated that expanding hVFG stem cells prior to further differentiation significantly enhances the efficiency of downstream lineage specification. This improvement is driven by the priming of organ-specific enhancers, mediated through dynamic regulation of chromatin accessibility, accompanied by the silencing of enhancers incompatible with the target lineage. 

Producing differentiated cells from stem cell progenitors not only significantly increases cell yield but also markedly improves the functional quality and maturity of the resulting cells. This strategy, mimicking human embryonic development, provides a deeper understanding of the mechanisms underlying early embryogenesis, especially how progenitor populations transition into specialized cell types. Moreover, it holds great promise for advancing regenerative medicine by enabling the generation of high-quality cells suitable for therapeutic applications and disease modeling. Currently, we are investigating the epigenetic mechanisms governing progenitor proliferation while developing organoid models of the hepato-pancreato-biliary system to explore the metabolic and epigenetic interactions within the digestive organs.