Publication highlights

Several models of cell fate lineages have been presented, some proposing a traditional straight path and others a more dynamic model, where cell fate remains more flexible. Researchers at the Crick combined a range of experimental techniques - single cell transcriptomics, quantitative live cell imaging and mathematical modelling - to track cell fate and determine which path is the right one. They found that there was no singular path, and these theories were not competing explanations but complementary snapshots of human development. The team also observed the influence of two important signalling molecules, Activin and BMP4, in determining which route cells would take between mesoderm or endoderm layers.

Cells need to be made in the right place at the right time in developing tissue, but how these two cues are coordinated to control cell identify is not well understood. Using mouse stem cell models of the neural tube, researchers at the Crick found a surprising "master clock" mechanism that modifies the chromatin of neural cells, making different DNA regions accessible at specific times during development. Working with the High Throughput Screening team, they identified key molecular regulators, including a transcription factor called Nr6a1, that control the temporal programme by altering chromatin accessibility. Disrupting these factors altered the identity of cells before and after becoming specialised. The ability of temporal factors in the mice to control chromatin accessibility over time explains how the same spatial progenitor domains can produce different cell types as development progresses. Taking into account the cell’s temporal clock could help engineer the generation of specific neurons and glial cells from stem cells for regenerative medicine purposes.

Researchers at UCL and the Francis Crick Institute have, for the first time, identified the origin of cardiac cells using 3D images of a heart forming in real-time, inside a living mouse embryo. The team used a technique called advanced light-sheet microscopy on a specially engineered mouse model, where a thin sheet of light is used to illuminate and take detailed pictures of tiny samples, creating clear 3D images without causing any damage to living tissue. They were able to track individual cells as they moved and divided over the course of two days – from a critical stage of development known as gastrulation through to the point where the primitive heart begins to take shape. This allowed the researchers to identify the cellular origins of the heart. The study’s findings could revolutionise how scientists understand and treat congenital heart defects.

Scientists at the Crick have generated human stem cell models which, for the first time, contain notochord – a tissue in the developing embryo that acts like a navigation system, directing cells where to build the spine and nervous system (the trunk). The team first analysed chicken embryos to understand exactly how the notochord forms naturally. By comparing this with existing published information from mouse and monkey embryos, they established the timing and sequence of the molecular signals needed to create notochord tissue. With this blueprint, they produced a precise sequence of chemical signals and used this to coax human stem cells into forming a notochord. The stem cells formed a miniature ‘trunk-like’ structure, which spontaneously elongated to 1-2 millimetres in length. The scientists believe this work could help to study birth defects affecting the spine and spinal cord.

Researchers at the Crick have developed a new method using single-cell techniques and AI to map how gene expression changes over time during cell fate decisions. They developed a metabolic labelling system called sci-FATE2 to generate high-quality data about the dynamics of gene activity in a single cell over time. They also developed new generative AI models to analyse the dataset. These methods were used to study the development of the mouse neural tube, by studying the differentiation of 45,000 embryonic stem cells. They found that this process occurs as two distinct fate decision points and were able to identify cells at the decision points and the genes involved in decision making. This new system could help to target and manipulate specific developmental events, which would contribute to the use of stem cells for disease modelling and regenerative medicine.

The Briscoe lab has used single cell mRNA sequencing to study the developing human spinal cord during gestational weeks 4 to 7. The team compared their results with the ones obtained in mice and found similarities as well as human-specific differences. This data is available as an open resource and will prove useful for future studies into sensory and motor control systems.