Electron scanning microscopy image showing a very detailed look at pieces of trunk organoids. Credit: Tiago Rito, Marie-Charlotte Domart
Researchers have made a significant advancement in studying early human development by successfully creating a lab-grown notochord, a key structural component in vertebrates.
This model, based on a carefully orchestrated sequence of chemical signals, mimics the human trunk’s early stages, complete with neural and bone stem cells. This breakthrough offers potential insights into spinal birth defects and intervertebral disc conditions, marking a new era for studying human developmental disorders.
Breakthrough in Human Development Research
Scientists at the Francis Crick Institute have created human stem cell models[1] that, for the first time, include the notochord — a tissue in the developing embryo that guides cells in forming the spine and nervous system (the trunk).
The research, published today (December 18) in Nature, marks a significant advancement in understanding how the human body forms during early development.
The notochord, a rod-shaped tissue, serves as a critical structural guide in the developing body. It is a defining feature of all vertebrates and plays a key role in organizing tissues as the embryo grows.
Due to its complexity, the notochord has been notably absent from previous lab-grown models of human trunk development, making this breakthrough especially important for advancing developmental biology.
Electron scanning microscopy image showing a very detailed look at pieces of trunk organoids. Credit: Tiago Rito, Marie-Charlotte Domart
Decoding the Notochord Formation
In this research, the scientists first analyzed 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.
Pieces of trunk organoids are fixed in tape. These samples will subsequently be coated with a thin layer of platinum and then imaged using electron microscopy. Credit: Tiago Rito, Marie-Charlotte Domart
Advancements in Lab-Grown Human Trunk Models
The stem cells formed a miniature ‘trunk-like’ structure, which spontaneously elongated to 1-2 millimeters in length. It contained developing neural tissue and bone stem cells, arranged in a pattern that mirrors development in human embryos. This suggested that the notochord was encouraging cells to become the right type of tissue at the right place at the right time.
The scientists believe this work could help to study birth defects affecting the spine and spinal cord. It could also provide insight into conditions affecting the intervertebral discs – the shock-absorbing cushions between vertebrae that develop from the notochord. These discs can cause back pain when they degenerate with age.
Detailed transparent video showing notochord cells (red) and the associated patterning molecules (in cyan) inside a trunk organoid. Cell nuclei in gray. Credit: Tiago Rito
Implications for Understanding Human Development
James Briscoe, Group Leader of the Developmental Dynamics Laboratory, and senior author of the study, said: “The notochord acts like a GPS for the developing embryo, helping to establish the body’s main axis and guiding the formation of the spine and nervous system. Until now, it’s been difficult to generate this vital tissue in the lab, limiting our ability to study human development and disorders. Now that we’ve created a model which works, this opens doors to study developmental conditions which we’ve been in the dark about.”
Microscopy image of the surface of a trunk organoid (right) and a computer-generated image (left) with notochord in green, surrounded by outer neural tissue (skeletonised in purple). Credit: Tiago Rito
Tiago Rito, Postdoctoral Fellow in the Developmental Dynamics Laboratory, and first author of the study, said: “Finding the exact chemical signals to produce notochord was like finding the right recipe. Previous attempts to grow the notochord in the lab may have failed because we didn’t understand the required timing to add the ingredients.
“What’s particularly exciting is that the notochord in our lab-grown structures appears to function similarly to how it would in a developing embryo. It sends out chemical signals that help organize surrounding tissue, just as it would during typical development.”
Section of a human trunk-organoid. The notochord (green) causes neural tissue (in blue) to be patterned (in magenta ). Cell nuclei stained in white. Credit: Tiago Rito
Notes
- These structures are simplified models of the body which contain only a small number of cell types. They develop for just a few days and cannot form embryos. Their main purpose is to study aspects of human development that have been difficult or impossible to investigate directly.
Reference: “Timely TGF-b signalling inhibition induces notochord” by Rito, Tiago. et al., 18 December 2024, Nature.
DOI: 10.1038/s41586-024-08332-w
