Jakob Lab: Redox and the Fate of Embryonic Stem Cells

Embryonic stem cells (ESCs) can develop into any cell type in the body. Yet, the regulatory mechanisms that govern cell fate decisions during embryogenesis remain largely unknown.

In a study published in Developmental Cell, MCDB researchers Agnes Ulfig and Ursula Jakob explain how ESC heterogeneity is generated and used by individual cells to decide between distinct cellular fates.

ESCs at the blastocyst stage exit pluripotency and differentiate to either mesendoderm (ME; progenitor of mesoderm and endoderm) or neuroectoderm (NE).

Their  study demonstrates that the fate of ME and NE at the onset of gastrulation is controlled by the individual mitochondrial reactive oxygen species level of the cells. They propose that these intercellular differences arise from region-specific variations in the oxygen level within the developing in vivo embryo.

"We demonstrate that a pluripotent mESC population exhibits striking cell-to-cell variations in both mitochondrial and nuclear redox states, which individualize cell fate. Mechanistic analysis revealed that mESCs with either oxidant-induced or naturally high mitochondrial ROS levels differentiate toward the ME, while mESCs, which generate less ROS, choose the NE lineage. Differentiation toward the ME fate is initiated by mitochondrial ROS-induced global reduction in H3K4me3 levels and the stabilization of the redox-sensitive transcriptional regulator p53. Subsequent activation of the ROS-sensitive transcriptional regulator Nrf2 promotes the restoration of a reduced nuclear redox state, which leads to the accumulation of H3K4me3 marks at a hitherto unknown p53 binding site of the Wnt3 gene. Subsequent induction of Wnt3 ligand expression induces the canonical Wnt signaling pathway and triggers ME-related gene expression. Our study thus provides insights into the mechanism by which heterogeneity in gene expression within an isogenic mESC population arises and is used by individual cells to undertake decision-making processes, ultimately leading to the development of cellular diversity during embryogenesis.”

Jakob is the Patricia S. Yaeger Collegiate Professor in Molecular, Cellular, and Developmental Biology. Agnes Ulfig is a postdoctoral researcher in the Jakob group.