Scientists at the University of Cambridge have created a small lab-built brain and spinal cord system that mimics the way motor signals pass through the human nervous system. Using this model, the research team discovered that nerve damage previously thought to be permanent may actually be reversible under certain conditions.
As the human body grows from fetus to fetus and finally to infant, neurons form a complex communication network between the brain and spinal cord. These signals travel through axons, long nerve fibers that allow neurons to send messages and control muscle movement.
However, over time, the central nervous system largely loses its ability to regenerate damaged axons. As a result, brain and spinal cord damage is often permanent and leads to serious disabilities such as paralysis and movement disorders. This loss of regenerative capacity is also associated with neurological diseases such as motor neuron disease and multiple sclerosis.
Mini human brain and spinal cord model
In 2021, Dr. Andras Lakatos and colleagues at the University of Cambridge developed a miniature human brain model using stem cells taken from patients. These pea-sized “brain organoids” resemble parts of the cerebral cortex, allowing researchers to study the molecular changes associated with motor neuron diseases and look for ways to prevent them.
Now, in a new study published in cell reportresearchers expanded on that work by building a miniature version of the connected human brain and spinal cord system.
Because the brain and spinal cord are separate but connected structures in the body, the researchers kept the organoids physically separated in the lab. They then observed that axons in the brain tissue grew across the gap and connected to the spinal cord tissue. The resulting neural circuit was functional enough to cause contractions of small clusters of muscle cells.
Nerve regrowth declines during development
Scientists maintained these small systems in the lab for more than a year. They found that damaged axons could still regenerate until about day 150 of development, which roughly corresponds to the second trimester. After that point, the neurons’ ability to regenerate decreased significantly.
“While neurons taken from immature organoids regenerated long fibers after injury, neurons taken from more mature organoids showed a sharp decline in regeneration capacity. In other words, human neurons maturing in the central nervous system have a built-in defect in regeneration,” said George Gibbons, lead author of the study, from the University of Cambridge’s Department of Clinical Neuroscience.
The research team analyzed the gene activity of neurons that connect the brain and spinal cord. Their research reveals a network of genes that act like biological switches, limiting axon growth as neurons mature and form synapses.
Remarkably, when the researchers blocked key regulators in this network, neurons regained the ability to grow axons.
Promoting nerve regrowth with existing drugs
The researchers also searched databases of drug compounds to identify drugs that affect this newly identified gene network. One promising candidate was linestrenol, a hormonal agent currently approved for certain menstrual disorders and as a contraceptive.
When the drug was tested on injured neurons, it significantly improved axon regrowth.
The scientists noted that scar tissue and inflammation can also impede nerve repair after injury. However, understanding the neuron-specific biological mechanisms that limit regeneration remains critical. Evidence so far indicates that younger neurons are able to grow through environments that normally prevent repair of damaged sites.
“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 paralysis is usually permanent,” said senior author Dr. Andras Lakatos, who led the study in the Department of Clinical Neuroscience.
“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.”
Why are human organoids important?
Organoid technology is becoming increasingly valuable in the study of human biology and disease. Although animal models such as mice and rats remain useful in research, important biological differences limit how accurately they reflect human nervous system function.
Human stem cell-derived organoids can more closely mimic human biology, helping to bridge the gap between animal studies and real-world patient outcomes.
Dr. Lakatos added, “Much of what we know about nerve regeneration comes from rodents, whose neurons 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.”
Researchers at the University of Cambridge are already using organoids in a wide range of medical research, including repairing damaged livers, investigating Crohn’s disease in children, and studying the early stages of pregnancy.
This research was funded by the UK Research, Innovation and Medical Research Council and Spine Research.
