Scientists at Cambridge have developed a miniature circuit in the lab that mimics the connections between the brain and spinal cord that underlie our movement. They used this model to show how damage to these connections, previously thought to be “irreversible,” is actually reversible.
As we develop and grow into fetuses, fetuses, and infants, nerve cells (neurons) form connections that allow information to be transmitted between the brain and spinal cord. A key component of each neuron is its axon. This is a “cable” of nerve fibers that transmits information to other neurons to activate muscle contraction.
At some point, we lose the ability to grow axons in the central nervous system, or this ability becomes at least significantly impaired or slowed down. This means that the damage to the brain and spinal cord is permanent and can lead to severe disabilities, such as the inability to grasp objects or walk. This is common in traumatic spinal cord injuries and may be a feature of many neurological diseases such as motor neuron disease and multiple sclerosis.
In 2021, Dr. Andras Lakatos and colleagues at the University of Cambridge developed “mini-brains” using stem cells from human patients – special cells that can grow into most human cell types – and induced them to grow into pea-sized brain “organoids”. These organoids were 3D models that resembled parts of the human cerebral cortex. The research team used these to demonstrate molecular problems in motor neuron diseases and possible ways to prevent them.
Now, in a study published in cell reportDr. Lakatos’ team took the research a step further and built mini-versions of the connected human brain and spinal cord system in the lab by using organoids to recreate these tissues.
In the human body, the brain and spinal cord tissues are separate but connected by axons, so the researchers kept the brain and spinal cord organoids separate. They determined that nerve fibers from the brain tissue grow across the gap and connect to the spinal cord, forming actuating circuits that can even contract small muscle masses.
When this human system was grown in culture dishes for more than a year, the researchers found that axons were able to regrow after injury until around day 150, which corresponds to the second trimester, but after that point, growth was severely impaired.
Neurons harvested from less mature organoids regenerated long fibers after injury, whereas neurons harvested from more mature organoids showed a sharp decline in regenerative capacity. In other words, human neurons that mature in the central nervous system have a built-in defect in regeneration. ”
George Gibbons, first author of the study, Department of Clinical Neuroscience, University of Cambridge
By analyzing gene expression (signs of gene activity) in neurons that connect the brain and spinal cord, researchers were able to identify a network of genes that act as “switches” that limit the ability of axons to grow while neurons mature and form connections (synapses). Remarkably, blocking key regulators of this network turned the axonal growth ability back on.
The team then scanned a database of drug compounds for compounds that act on genes in this network and identified linestrenol, a hormonal drug approved for the management of certain menstrual disorders and as a contraceptive, as a candidate. When the drug was tested on damaged neurons, it was found to significantly promote axonal regrowth.
Although scar tissue and inflammation can also limit axonal repair, it is critical to explore and address the neuron-specific causes, which are the subject of this study. This is supported by evidence that the axons of less mature neurons can grow through the nonpermissive environment that is characteristic of the injury site.
“When the brain and spinal cord are injured, the nerve fibers that carry motor signals from the brain to the spinal cord rarely recover, so the paralysis is usually permanent,” said senior author Dr. Andras Lakatos, who led the project in the Department of Clinical Neuroscience. “However, we did not know exactly when the ability of axons to regenerate is limited. Our model provides a good indication that this block occurs during development and can be recovered past this point.”
“Linestrenol itself may not be a solution for spinal cord repair, but our results show that in principle it should be possible to directly target neurons in humans and regenerate their axons. We still need to show that this strategy also helps re-establish proper connections between brain and spinal cord cells, but this gives us hope that one day we might be able to treat conditions previously thought to be untreatable.”
Organoid models are an important way to understand human biology. Animal models such as mice and rats are useful for studying biology because they share some similarities with humans, but their differences ultimately limit what we can learn. Organoids grown from human stem cells can more closely mimic human biology.
Dr. Lakatos added, “Much of what we know about nerve regeneration comes from rodent neurons, which behave differently than human neurons. Our sophisticated organoid model helps bridge the gap in knowledge from animal models to what is observed in patients. It is also an important contribution to efforts to reduce the use of animals in research.”
Organoids, also known as “mini-organs,” are increasingly used to model human biology and disease. At the University of Cambridge alone, researchers are using them in a number of applications, including repairing damaged livers, understanding Crohn’s disease in children, and modeling early stages of pregnancy.
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Reference magazines:
Gibbons GM, others (2026). The human corticospinal organoid slice connectoid model provides an enhancer strategy for axonal regrowth after injury. cell report. DOI: 10.1016/j.celrep.2026.117399. https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00477-8.
