Author: Naomi Choi
Editor: Milly Mak
Artist: Ahmad Bilal
Think dopamine just brings happiness? In fact, this brain chemical does much more. Dopamine is a crucial neurotransmitter in the brain, and there are specific nerve cells that produce dopamine — dopaminergic neurones. Although dopaminergic neurones make up less than 1% of all brain neurones, they play a vital role in brain function, controlling aspects such as motivation, habit learning, and motor control. However, dopaminergic neurones are especially vulnerable to degeneration since they require a lot of energy to send nerve signals along their extensive branching networks, and this degeneration is thought to play a role in the development of Parkinson’s disease, an incurable neurodegenerative disorder characterised by the progressive loss of dopaminergic neurones. Parkinson’s is the fastest-growing neurological condition, affecting around 10 million individuals worldwide and estimated to double by 2050.
Current treatments for Parkinson’s focus on managing and minimising symptoms, but researchers are exploring approaches to slow, stop, or even reverse the disease’s progression. One potential solution is via stem cell therapy, where stem-cell-derived dopaminergic neurones are transplanted into the brains of patients as a treatment for the disorder.
Regulatory T Cells: The Body’s Immune Peacekeepers
In order for this treatment to be effective, dopaminergic neurones must survive the implantation process. However, research conducted by Park and his colleagues, a research team at Harvard Medical School, has shown that over 90% of these neurones die within two weeks of implantation in animal trials, mostly due to inflammatory responses triggered by the surgery itself. More importantly, this inflammatory cascade also makes the grafted foreign cells more visible to the immune system, leading to rejection. Thus, for stem-cell therapy to work, the main challenge for scientists is finding a way to protect and shield these dopaminergic neurones from the body’s immune defences.
To tackle this problem, researchers have turned to regulatory T cells, or Tregs — a unique and specialised subpopulation of helper T-cells known for their role in maintaining immune equilibrium. These immune cells help prevent autoimmune attacks by suppressing immune responses, constraining immune activation, and promoting tissue repair. It is also shown that when Tregs are co-transplanted with stem-cell-derived dopaminergic neurones, Tregs significantly enhance neurone survival.
To make things simpler, let us compare the traditional implantation method with the co-transplantation method. In the traditional method, where only stem-cell-derived dopaminergic neurones are implanted, the process of injecting the neurones into the body causes a local immune response. Immune cells like myeloid and natural killer (NK) cells flood the transplant site, secreting proinflammatory molecules such as tumour necrosis factors (TNFs), interleukin-1 (IL-1), and interferon gamma (IFN-γ), which can kill neurones. This inflammatory environment also induces the spread of progenitor cells — immature implanted cells that have not fully differentiated yet. This proliferation is undesirable, since progenitor cells could unpredictably differentiate into various types of cells including tumour cells, leading to more inflammatory response and disrupting the implantation process. However, if Tregs are implemented, the outcome is far more promising, as they have successfully reduced inflammation and proliferation of progenitor cells.
Why the Environment Matters: Oxygen and Nutrient Challenges
However, immune rejection is not the only challenge, since dopaminergic neurones face environmental stress as well. These neurones are typically produced and cultured in an environment with an oxygen concentration of ~21%, whereas the oxygen level inside brain tissue is only around 1-5%. This steep drop in oxygen availability, along with the sudden reduction of nutrients, causes cellular stress, triggering inflammation and rapid cell death. In fact, a study by Park et al. has shown that 90% of transplanted neurones are lost even with minimal immune rejection; thus, poor cell survival remains a major obstacle.
One intuitive approach might be to simply transplant more cells to account for the loss. However, increasing cell numbers leads to greater competition for the already limited resources, ultimately worsening the problem rather than resolving it. This is why regulatory T cells play a dual role here; not only do they reduce immune response, but they also create a more hospitable microenvironment, helping the transplanted neurones withstand the harsh conditions.
Unlike conventional anti-inflammatory drugs, Tregs adapt to the changing environment caused by inflammatory molecules post-surgery, allowing Tregs to utilise various mechanisms and making them especially effective in protecting the implanted cells. Another additional benefit of Tregs is their ability to act locally and work precisely where they are needed, helping to prevent generalised immunosuppression occurring in other parts of the body. Although co-transplanting Tregs would make the process more complex, only a small number of Tregs are needed since it is location-specific and highly targeted, making this technique more efficient.
The Future of Treg-Enhanced Stem-Cell Therapy
Treg-enhanced stem cell therapy is promising as a potential treatment for Parkinson’s due to Tregs’ anti-inflammatory, adaptive, and highly targeted nature. This pioneering discovery by Park et al. is undoubtedly a breakthrough for Parkinson’s, but it has also opened up possibilities to treating other neurodegenerative disorders. While Treg-enhanced stem cell therapy is still in experimental stages, its utilisation could be transformative in improving the viability of stem-cell therapies. As science continues to unlock the potential of Tregs, we move closer to realising more regenerative therapies that could one day profoundly impact and save the lives of millions.
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