It is generally well-known that the adult brain has a limited capacity to regenerate or repair itself after injury, like that caused by trauma or strokes, or regenerative diseases like Parkinson’s Disease (PD). Transplantation of neural stem cells to replace lost neuronal function (cell therapy) holds promise for neurological disorders, but the brain’s finely tuned complexity has impeded the development of clinical treatments.
For cell therapy to succeed, grafted neuronal progenitors (early descendants of stem cells) need to differentiate into specific types of neurons that send out axons through the mature central nervous system environment to find and make functional synaptic connections with their target. Furthermore, grafted neurons should receive proper input from host neurons so that the activity of the grafted cells is regulated appropriately. Together, the grafted cells replace the lost neurons and restore circuit function. Although cell transplantation can rescue motor defects in PD models, whether and how grafts functionally repair damaged neural circuitry in the adult brain is not known. The researchers of this paper tested this out on a mouse model.
To repair those damaged circuits in the PD mouse model, the researchers transplanted human embryonic stem cell-derived midbrain dopamine or cortical glutamate neurons into the substantia nigra or striatum of a mouse PD model and found extensive graft integration with host circuitry. The substantia nigra is an important player in brain function, in particular, in eye movement, motor planning, reward-seeking, learning, and addiction. Many of the substantia nigra’s effects are mediated through the striatum, and in PD patients the dopamine neurons in the nigro-striatal pathway degenerates (the nigro-striatal pathway is one of four dopaminergic pathways in the brain, and it connects the substantia nigra in the midbrain with the striatum in the forebrain).
The researchers were able to see that the transplanted neurons grew long distances to connect to motor-control regions of the brain. The nerve cells also established connections with regulatory regions of the brain that fed into the new neurons and prevented them from being overstimulated. Both sets of connections — feeding in and out of the transplanted neurons (pre- and post-synaptic integration) — resembled the circuitry established by native host neurons. This was only true for dopamine-producing cells. Similar experiments with cells producing the neurotransmitter glutamate, which is not involved in PD, did not repair motor circuits, revealing the importance of neuron identity in repairing damage.
To finally confirm that the transplanted neurons had repaired the Parkinson’s-damaged circuits, the researchers inserted genetic on-and-off switches into the stem cells. These switches turn the cells’ activity up or down when they are exposed to specialised designer drugs in the diet or through an injection. When the stem cells were shut down, the mice’s motor improvements vanished, suggesting that the stem cells were essential for restoring Parkinson’s-damaged brains. It also showed that this genetic switch technology could be used to fine-tune the activity of transplanted cells to optimise treatment.
Through this experiment, the researchers found that neurons derived from stem cells can integrate well into the correct regions of the brain, connect with native neurons and restore motor functions. The key is identity. By carefully tracking the fate of transplanted stem cells, the scientists found that the cells’ identity — dopamine-producing cells in the case of Parkinson’s — defined the connections they made and how they functioned.
Original Source: M Xiong, Y Tao, Q Gao, et. al. “Human Stem Cell-Derived Neurons Repair Circuits and Restore Neural Function” 2020. Cell Stem Cell.
Original Link: https://doi.org/10.1016/j.stem.2020.08.014