Unveiling Human Stem Cell Model with Functional Notochord

For the first time, notochord, a tissue in the developing embryo that serves as a navigation system, telling cells where to build the spine and nervous system (the trunk), has been included in human stem cell models created by researchers at the Francis Crick Institute.

The study, published in Nature, represents a major advancement in our understanding of how the human body develops in its early stages.

One of the most important components of the developing body's scaffold is the rod-shaped tissue known as the notochord. This characteristic distinguishes all animals with backbones and is essential for the organization of tissue in the growing embryo.

Despite its significance, the structure's complexity has prevented it from being included in earlier laboratory-grown models of human trunk development.

To determine precisely how the notochord forms naturally, the researchers in this study first examined chicken embryos. They determined the timing and order of the molecular signals required to form notochord tissue by contrasting this with previously published data from mouse and monkey embryos.

They used this blueprint to create a precise chemical signal sequence that induced human stem cells to form a notochord.

A tiny “trunk-like” structure was created by the stem cells, and it naturally grew to be 1-2 mm long. It included bone stem cells and growing neural tissue, arranged in a manner similar to how human embryos develop. This implied that the notochord was promoting cells to develop into the appropriate tissue type at the appropriate time and location.

The researchers think that this work may aid in the study of spinal cord and spine birth defects. Additionally, it might shed light on disorders affecting the intervertebral discs, which are the shock-absorbing cushions that grow from the notochord between vertebrae. When these discs deteriorate with age, back pain may result.

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 is been difficult to generate this vital tissue in the lab, limiting our ability to study human development and disorders. Now that we have created a model which works, this opens doors to study developmental conditions which we have been in the dark about.”

James Briscoe, Group Leader and Study Senior Author, Developmental Dynamics Laboratory, Francis Crick Institute

Tiago Rito, Postdoctoral Fellow in the Developmental Dynamics Laboratory, and Study First Author 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 did not understand the required timing to add the ingredients. What is 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.”

Notochord cells (red) and the associated patterning molecules (in cyan) inside a trunk organoid. Cell nuclei in gray. Video Credit: Tiago Rito