Lab-grown brain-spinal cord model shows ‘irreversible’ nerve damage may be reversed | University of Cambridge
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Lab-grown brain-spinal cord model shows ‘irreversible’ nerve damage may be reversed
Cambridge scientists have grown miniature circuits in the lab that mimic how the brain and spinal cord connect up, which underlies our movements. They used this model to show how damage to these connections previously considered ‘irreversible’ could, in fact, be reversible.
Our sophisticated organoid models help bridge the knowledge gap from animal models to what we see in patients.
András Lakatos
As we develop and grow from embryo to fetus to infant, our nerve cells (neurons) form connections, allowing information to be transmitted between the brain and the spinal cord. A key component of each neuron is the axon – the nerve fibre ‘cable’ that transmits information to other neurons to activate muscle contractions.<br>At some point, we lose the ability to grow axons in the central nervous system, or this ability is at least greatly impaired or slowed down. This means that damage to the brain and spinal cord becomes permanent, leading to devastating disabilities, such as the inability to grasp or walk. This is often the case for traumatic spinal cord injury and can be a feature of many neurological diseases, including motor neurone disease or multiple sclerosis.<br>In 2021, Dr András Lakatos and colleagues at the University of Cambridge developed ‘mini brains’ using human patient-derived stem cells – special cells that have the potential to develop into most human cell types – which they guided to grow into pea-sized brain ‘organoids’. These organoids were 3D models that resemble parts of the human cerebral cortex. The team used these to demonstrate molecular problems in motor neurone disease and potential ways to prevent them.<br>Now, in research published in Cell Reports, Dr Lakatos’s team has taken its research a step further, building a mini version of the connected human brain and spinal cord system in the lab by recreating these tissues using organoids.<br>In the human body, the brain and spinal cord tissues are distinct but connected by axons, so the researchers kept the brain and spinal cord organoids apart. They saw that nerve fibres from the brain tissue grew across the gap to connect to the spinal cord, forming a working circuit that could even cause tiny muscle clusters to contract.<br>By growing this human system in the dish for more than a year, they found that up until around day 150 – which corresponds to the mid-trimester of pregnancy – the axons were able to regrow after damage, but after this time, their growth was greatly impaired.<br>George Gibbons from the Department of Clinical Neurosciences at the University of Cambridge, the study’s first author, said: “Neurons taken from less mature organoids regrew long fibres after injury, but those from more mature organoids showed a sharp drop in their ability to regrow. In other words, poor regeneration is built into human neurons as they mature in the central nervous system.”<br>By analysing the gene expression – a sign of how active the genes are – in neurons that connect the brain and the spinal cord, they were able to identify a network of genes that acts as a ‘switch’ restricting the axon growth ability while the neurons mature to form connections (synapses). Amazingly, blocking key regulators of this network switched back on the ability of axons to grow.<br>The team then scanned a database of drug compounds to search for those that act on the genes in this network and identified as a candidate lynestrenol, a hormone drug licensed for managing certain menstrual disorders and as a contraceptive. When they tried this drug on damaged neurons, they found that it significantly boosted axon regrowth.<br>While scar tissue and inflammation may also restrict axon repair, exploring and...