Summary: Neurons derived from stem cells can integrate into the appropriate brain regions, form functional connections with native neurons, and restore motor function in mouse models of Parkinson’s disease.
Source: University of Wisconsin–Madison
The adult brain has a very limited ability to repair itself after injury, stroke, or neurodegenerative diseases such as Parkinson’s. Stem cells, with their capacity to become many different cell types, hold promise for rebuilding damaged neural circuits. However, translating that potential into reliable clinical treatments has been difficult because the brain’s circuitry is exquisitely specific and highly organized.
In new work addressing these challenges, researchers at the University of Wisconsin–Madison report a proof-of-concept stem cell therapy in a mouse model of Parkinson’s disease. They show that human embryonic stem cell–derived neurons can adopt the correct identities, integrate into host neural networks, form appropriate connections, and restore motor behaviors impaired by Parkinsonian damage.
A central finding of the study is the importance of neuronal identity. By labeling and tracking transplanted cells over time, the investigators determined that the specific type of neuron produced from stem cells — in this case, dopamine-producing midbrain neurons — dictates both the pattern of anatomical connections they make and their functional role in the host brain.
Advances in stem cell differentiation techniques now allow researchers to produce many distinct neuron subtypes in the lab. According to the authors, these methods combined with the new evidence for precise circuit integration make targeted neural stem cell therapy a realistic long-term goal, although significant work remains to move from animal models to human patients.
The study, led by neuroscientist Su-Chun Zhang at UW–Madison’s Waisman Center, appears in the journal Cell Stem Cell. The experiments were conducted by members of Zhang’s laboratory, including postdoctoral researchers who contributed to the project and are now faculty in China and Singapore.
“Our brains rely on highly specialized nerve cells located in precise regions to enable complex behaviors,” says Zhang, professor of neuroscience and neurology. “Neurological injuries and diseases often affect particular cell types or regions, disrupting circuits. Effective repair requires restoring those specific circuits.”
To reconstruct damaged circuits in a mouse Parkinson’s model, the team guided human embryonic stem cells to differentiate into midbrain dopamine neurons — the cell type that degenerates in Parkinson’s disease. They transplanted these neurons into the midbrain areas most affected by Parkinsonian degeneration.
After several months, the transplanted neurons had extended long axons and integrated into the host brain. Mice receiving the dopamine neurons showed improvements in motor performance. Detailed analysis revealed that grafted cells projected to motor-control regions and also received regulatory inputs from brain areas that normally modulate dopaminergic neurons, helping prevent overstimulation.
Both incoming and outgoing connections made by the transplanted dopamine neurons closely resembled those of native midbrain neurons. By contrast, when the researchers transplanted stem cell–derived glutamatergic cortical neurons — which are not the type lost in Parkinson’s — the grafts did not reconstitute the motor circuits or restore motor function. This contrast underscores that the correct neuronal subtype is essential for circuit repair.
To demonstrate that the grafted neurons were responsible for the behavioral recovery, the team introduced genetic “on-off” switches into the transplanted cells. These switches allow researchers to selectively suppress or activate graft activity using designer drugs. Silencing the transplanted neurons eliminated the motor improvements, confirming that the grafts were functionally necessary for recovery and showing that cell activity can be modulated to optimize outcomes.
Zhang and collaborators have developed protocols for producing multiple neuron subtypes from human pluripotent stem cells. While each neurological disorder may require a tailored cell type for effective repair, the overall therapeutic approach—differentiating stem cells into the required neuronal subtype, transplanting them into the damaged region, and ensuring appropriate connectivity—would be broadly similar across conditions.
The research also carries personal significance for Zhang. As a clinician-scientist he often hears from families seeking treatments for neurological disorders and brain injuries. Zhang himself was seriously injured in a cycling accident six years ago and faced partial paralysis; his recovery involved prolonged rehabilitation and reinforced his conviction that the right stem cell therapies could one day help patients facing similar challenges.
Building on the mouse work, Zhang’s team is testing related stem cell interventions in nonhuman primates as a step toward assessing safety and efficacy before potential human trials. “There is hope, but we must proceed step by step,” he emphasizes.
Funding: This research was supported in part by the National Institutes of Health (grants NS096282, NS076352, NS086604, MH099587 and MH100031).
About this research article
Source:
University of Wisconsin–Madison
Contacts:
Su-Chun Zhang – University of Wisconsin–Madison
Image Source:
The image is in the public domain.
Original Research: Closed access.
“Human Stem Cell-Derived Neurons Repair Circuits and Restore Neural Function” by Su-Chun Zhang et al., Cell Stem Cell. DOI: 10.1016/j.stem.2020.08.014
Abstract
Human Stem Cell-Derived Neurons Repair Circuits and Restore Neural Function
Although cell transplantation can rescue motor defects in Parkinson’s disease models, whether and how grafts functionally repair damaged neural circuitry in the adult brain is not fully understood. In this study, human embryonic stem cell–derived midbrain dopamine (mDA) neurons or cortical glutamatergic neurons were transplanted into the substantia nigra or striatum of a mouse Parkinson’s model, and extensive graft integration with host circuitry was observed. Axonal pathfinding toward the dorsal striatum depended on the identity of grafted neurons. Presynaptic inputs were influenced principally by graft location, while the balance of inhibitory versus excitatory input was dictated by neuronal identity. hESC-derived mDA neurons exhibited A9 characteristics and restored function of the reconstructed nigrostriatal circuit, leading to improved motor behavior. These results highlight the capacity of human pluripotent stem cell–derived neuron subtypes for specific circuit repair and functional restoration in the adult brain.