Amazing stuff! Are we finally understanding the development of the human brain a little better.
"Just a few weeks after conception, stem cells are already orchestrating the future structure of the human brain. A new Yale-led study shows that, early in development, molecular “traffic cops” known as morphogens regulate the activation of gene programs that initiate stem cells’ differentiation into more specialized brain cells. ...
The team ... developed a device called Duo-MAPs, which allowed them to expose organoids derived from human stem cells to two crucial morphogens naturally present within the developing brain. The WNT morphogen, active along the posterior-anterior (bottom to top) axis of the nascent central nervous system, interacts with the Sonic Hedgehog morphogen, which operates along ventro-dorsal (front to back) axis of developing nervous system.
Together, the location and concentrations of the two morphogens over just 5 days regulated the gene activity that determined the eventual structure and cell composition of almost all brain regions, the researchers found.
Intriguingly, the high-throughput analysis enabled by the device showed distinct differences in the two morphogens’ gene activity in organoids derived from different individuals and different stem cell lines. For instance, organoids from some stem cell lines showed higher sensitivity to the WNT morphogen and the activated genes were concentrated towards the bottom of the brain where the hindbrain develops.
Other lines showed lower sensitivity to WNT and activity shifted toward anterior or frontal brain areas, such as the developing cortex. Similarly, stem cell lines more sensitive to Sonic Hedgehog showed higher gene activity in the developing basal ganglia, while stem cells less sensitive to the morphogen had a greater gene response in the developing cerebellum. The morphogen-response genes that were most variable among different donors involved functions such as immune response, other experiments showed. ..."
From the highlights and abstract:
"Highlights
• Orthogonal WNTs/SHH gradients pattern organoids into forebrain, midbrain, and hindbrain
• WNT/SHH crosstalk triggers transcriptional programs driving lineage specification
• There are donor- and line-specific variations in morphogen response
• Patterned regions generate neuronal networks with different functional organization
Summary
The repertoire of neurons and their progenitors depends on their location along the antero-posterior and dorso-ventral axes of the neural tube.
To model these axes, we designed the Dual Orthogonal-Morphogen Assisted Patterning System (Duo-MAPS) diffusion device to expose spheres of induced pluripotent stem cells (iPSCs) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively.
Comparison with single-cell transcriptomes from the fetal human brain revealed that Duo-MAPS-patterned organoids generated an extensive diversity of neuronal lineages from the forebrain, midbrain, and hindbrain.
WNT and SHH crosstalk translated into early patterns of gene expression programs associated with the generation of specific brain lineages with distinct functional networks.
Human iPSC lines showed substantial interindividual and line-to-line variations in their response to morphogens, highlighting that genetic and epigenetic variations may influence regional specification.
Morphogen gradients promise to be a key approach to model the brain in its entirety."
Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines (no public access)
Specification of human regional brain lineages using orthogonal gradients of WNT and SHH in organoids (preprint, published about one year earlier, open access)
Graphical abstract
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