Human organoids suggest that 'irreversible' nerve damage might be reversed

A developmental mechanism that restricts nerve regeneration has been identified using neural organoids.

Researchers at the University of Cambridge developed an assembly of brain and spinal cord organoids that mimic the neural circuits of the human central nervous system. They differentiated human embryonic stem (ES) cells into brain and spinal cord tissue, which self-organised into connected organoids. Organoids are three-dimensional cell cultures that model aspects of the structure and function of human organs. Using the organoids, the researchers investigated why nerve cells in the central nervous system lose their ability to regenerate during development.

'When the brain and spinal cord are damaged, the nerve fibres that carry movement signals from the brain to the spinal cord rarely grow back. That's why paralysis is usually permanent,' said Dr András Lakatos from the Department of Clinical Neurosciences at the University of Cambridge and senior author of the study published in Cell Reports. 'Our model provides a good indication that this block happens during development, and it can still be reversed after this point.'

The team focused on corticospinal-like neurons present in their organoids. In the body, corticospinal neurons extend from the brain to the spinal cord and are essential for controlling voluntary movement. When their axons – the long cell projections that transmit signals to other neurons or to muscles – are damaged, these rarely regenerate. To investigate why this regenerative ability is lost, the researchers compared younger and more mature brain-spinal cord organoids after inducing injury to corticospinal axons.

The results showed that axons in more mature organoids had a much lower capacity for regrowth than those in younger organoids. The researchers identified FGF2 signalling as a developmental mechanism underlying this loss of regenerative ability. Blocking FGF2 signalling restored axon regrowth in the mature organoids.

'Today, we are entering a new era of hope and possibility for the 15 million people worldwide living with a spinal cord injury,' said Louisa McGinn, chief executive of Spinal Research. 'The next five years present an unprecedented opportunity to change what's possible for people living with spinal cord injuries. Breakthrough therapies are nearing clinical reality, and frontier technologies are creating bold new pathways toward repair and recovery.'

Although many other factors, including scar tissue and immune responses, also limit nerve regeneration after spinal cord injury, the study provides new insight into why regenerative capacity declines during development. The researchers conclude that their organoid model provides a way to investigate mechanisms that limit nerve regeneration and to evaluate potential strategies for promoting axon regrowth.