Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

The Generation of Positional Identity in Mesendoderm; Mechanism(s) of Lineage Specification in Vertebrate Development

Funder MRC (part of UKRI)
Recipient organisation University of Edinburgh
Funding £1.6M
Period Apr 2008 — Dec 2013

In plain English

AI plain-English summary

Cells destined to become the gut and its associated organs send signals to the developing nervous system as they migrate along the embryo’s midline, but the molecular instructions that drive this process remain poorly understood. This matters because scientists cannot yet reliably direct human embryonic stem cells to become specific gut-derived organs like the liver or pancreas. The embryo’s complex, shifting environment makes it nearly impossible to isolate and study the precise sequence of molecular events that turn a generic cell into a specialised organ precursor. Without that fundamental understanding, efforts to grow transplantable tissues in the lab remain hit-or-miss. The researchers have built a system that solves this problem. They engineered mouse embryonic stem cells that glow when they commit to becoming gut tissue, and grew them as a flat monolayer on plastic. This allows the team to swap chemical signals in the culture medium and watch differentiation happen in real time. This is fundamental science. It will not produce a therapy next year. But by defining the exact molecular triggers that drive each step of gut and organ formation, the work could eventually provide the recipe for growing functional liver or pancreatic tissue from stem cells—something that remains out of reach today.

View original technical description
During early embryonic development, the cells of the future gut move along the midline of the embryo signalling to the nervous system. To understand the molecular instructions driving the differentiation of these cells it is necessary to isolate them from the complex and changing environments in the embryo. Being able to break down this in vivo process of lineage specification is also essential for the generation of gut associated cell types and organs from human ES cells. In this proposal, we utilise genetically modified mouse ES cells that report on differentiation towards the embryonic gut in real time. We have used this system to generate monolayer conditions for ES cell differentiation toward embryonic gut. Our ability to differentiate these cells attached to plastic means that we can easily change media components as well as following differentiation visually. This proposal exploits this system alongside embryonic models to tease apart the stages of differentiation. It contains a program of work that is both focused on identifying new determinants and understanding how these determinants drive differentiation. This proposal will provide basic mechanistic insight into developmental biology and define conditions for the efficient differentiation of ES cells towards organs like the liver and pancreas.

View the original record at the funder ↗

Researchers

Josh Brickman (Principal Investigator)

Related Research

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Integrating developmental pathways and chromatin structure during lineage specifcation
Integrating developmental pathways and chromatin structure during lineage specification
Prospective isolation of intermediate states during lineage commitment
Epigenetic regulation of cell fate during early mammalian development
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Original classification

Fellowship

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