Neurons from stem cells replace damaged neurons, precisely rewiring into the brain

October 28, 2016

As shown in this in vivo two-photon image, neuronal transplants (blue) connect with host neurons (yellow) in the adult mouse brain in a highly specific manner, rebuilding neural networks lost upon injury. (credit: Sofia Grade/LMU/Helmholtz Zentrum München)

Embryonic neural stem cells transplanted into damaged areas of the visual cortex of adult mice were able to differentiate into pyramidal cells — forming normal synaptic connections, responding to visual stimuli, and integrating into neural networks — researchers at LMU Munich, the Max Planck Institute for Neurobiology in Martinsried and the Helmholtz Zentrum München have demonstrated.

The adult human brain has very little ability to compensate for nerve-cell loss, so biomedical researchers and clinicians are exploring the possibility of using transplanted nerve cells to replace neurons that have been irreparably damaged as a result of trauma or disease, leading to a lifelong neurological deficit.

Previous studies have suggested there is potential to remedy at least some of the clinical symptoms resulting from acquired brain disease through the transplantation of fetal nerve cells into damaged neuronal networks. However, it has not been clear whether transplanted intact neurons could be sufficiently integrated to result in restored function of the damaged network.

Stem-cell-derived neurons mirror connections of damaged neurons

Now, in study published in Nature, the researchers have found that transplanted embryonic nerve cells properly differentiated into pyramidal cells, forming normal synaptic connections, responding to visual stimuli, and carrying out the tasks performed by the damaged cells (videos here).

The researchers were also “astounded” to find that the replacement neurons grew axons throughout the adult brain, reaching proper target areas, and receiving V1-specific (from the primary visual cortex) inputs from host neurons — precisely the same inputs that the original neurons had received.

This includes neocortical circuits that normally never incorporate new neurons in the adult brain.

In addition, after 2–3 months, the transplanted neurons were fully integrated in the brain, showing functional properties indistinguishable from the original neurons.

The study was supported by funding from the German Research Foundation (DFG). 

Abstract of Transplanted embryonic neurons integrate into adult neocortical circuits

The ability of the adult mammalian brain to compensate for neuronal loss caused by injury or disease is very limited. Transplantation aims to replace lost neurons, but the extent to which new neurons can integrate into existing circuits is unknown. Here, using chronic in vivo two-photon imaging, we show that embryonic neurons transplanted into the visual cortex of adult mice mature into bona fide pyramidal cells with selective pruning of basal dendrites, achieving adult-like densities of dendritic spines and axonal boutons within 4–8 weeks. Monosynaptic tracing experiments reveal that grafted neurons receive area-specific, afferent inputs matching those of pyramidal neurons in the normal visual cortex, including topographically organized geniculo-cortical connections. Furthermore, stimulus-selective responses refine over the course of many weeks and finally become indistinguishable from those of host neurons. Thus, grafted neurons can integrate with great specificity into neocortical circuits that normally never incorporate new neurons in the adult brain.