Beatrice Han

Restoring the MIND

Stem Cell Therapy and Neurodegenerative Diseases

Written By Beatrice Han Designed By Avi Singh

Few diseases are as terrifying as neurodegenerative diseases. Classifi ed as disorders that target the central or peripheral nervous system, neurodegenerative diseases are amongst the most diffi cult disorders for patients, doctors, and researchers.1 Without long term symptomatic relief from existing treatments, these diseases place the healthcare system under considerable strain.2 Of all the conditions encompassed by the broad umbrella of neurodegenerative disease, Huntington’s disease (HD) and Parkinson’s disease (PD) are two common disorders that affect seven million people worldwide.2 Each disease has unique molecular mechanisms that present challenges to existing modes of treatment.

Huntington’s disease is an inherited disease linked to a dominant genetic mutation that triggers the production of toxic proteins that kill medium spiny neurons, a type of neuron that performs the crucial function of receiving dopamine signals.3 Unlike Huntington’s disease, which induces damage to receptor cells, Parkinson’s disease is characterized by a loss of dopamine-supplying (DA) neurons due to an accumulation of misfolded proteins. This may alter the cellular environment enough to damage DNA and compromise neuron survival.3 Huntington’s disease patients generally suffer neuropsychiatric symptoms, while PD patients are affected by both motor and psychiatric symptoms. Both diseases are considered “incurable,” in that current treatments are only stop-gap measures, toothless against the inevitable breakdown of the brain. Even symptomatic-relief care for PD sometimes fails, as the strategy of supplying pharmaceutical agents that convert to dopamine in the brain suffers from declining effi cacy over time. Worse, it triggers adverse side effects, including worsening motor control and impulse control disorders.4

Fortunately, stem cell therapies offer an alternative option. Stem cells differentiate into many other cell lines and have the capacity to restore lost neurons and repair damaged cellular environments. For HD especially, marked by the loss of a specifi c cell line, stem cell therapy is an especially attractive option. With no natural consistent source of neurogenesis in the central nervous system, where most neurodegenerative diseases are localized, the need for stem cell therapies is especially urgent.5

Mesenchymal stem cells (MSCs) provide a promising solution for neurodegenerative disease treatment with their ability to differentiate into non-mesoderm derived cells like neurons. Unlike embryonic stem cells–the prototypical stem cell with almost unlimited differentiation capacity–MSCs are adult stem cells taken from mesodermal tissue, including bone, cartilage, and muscle.5 MSCs sidestep the thorny ethical controversies that plague ESCs, which face pushback because they are sourced from fetal tissue.2

Because MSCs display the unique capacity to “home” in on injured tissues, they are considered promising targets for future treatments.7 This selectivity is especially important because MSCs may be able to cross the blood brain barrier–which

usually prohibits therapeutic agents from entering the brain –allowing them to localize to injury sites and exert a full therapeutic effect.2

Once in the brain, MSCs address neurodegeneration through a two-fold response. First, MSCs can differentiate into neuron-like cells once exposed to specifi c environmental conditions, allowing them to directly replace lost neurons. Indeed, when rats displaying the motor symptoms of PD were implanted with a meshwork of MSCs, motor function improved because the transplanted MSCs differentiated into DA neurons, targeting the root of the dopamine defi ciency in PD.7 Second, beyond directly replacing DA neurons, MSCs can exert an immunomodulatory and neurotrophic effect; they secrete trophic factors, which are chemicals that promote the growth of neurons and protect existing neurons from degeneration. Trials in rodents manipulated to express the symptoms of HD have even indicated MSCs can be genetically modifi ed to secrete more of these trophic factors, creating a favorable extracellular environment to stave off degeneration.3 Many of these studies, which engineered MSCs to secrete excess trophic factor, saw the new treatment prolong their subject’s lives and reduce behavioral abnormalities associated with HD.4

Although many of the trials involving MSCs have taken place in animals, clinical trials in humans have been conducted, with varying outcomes. Some trials have concluded MSCs yielded positive outcomes with enrichment in DA-neuron tissue with 24 year survival, improvement of motor symptoms, and integration of MSCS into surrounding neural circuits.5 However, because of an inconsistent supply of MSCs and the heterogeneous nature of many transplants, which are derived from multiple donors, clinical results have been inconsistent.5 Indeed, deriving non-heterogeneous cell lines for grafts and transplants remains a pressing challenge, as pooling cells from multiple donors for transplants makes it diffi cult to source enough tissue for widespread clinical applications while rendering results extremely inconsistent. Regulation of the unpredictable immune responses to grafts of stem cells poses another threat to stem cell transplantation. Triggered by both the act of grafting itself–which is inherently surgically intrusive–and the presence of foreign cells in a host body, these immune responses may further infl ame the nervous system or reject the transplanted stem cell altogether, negating what therapeutic benefi t the treatment may have been achieved.3,8 Other challenges include ensuring the differentiated neuron properly interacts with the brain environment. To restore a damaged pathway, it is not enough to implant a cell without triggering an adverse response, as the cell must survive and regrow its axon to the targeted region. Because of the diffi culties associated with ensuring the correct connections are made, many clinical and animal trials have yielded inconsistent functional recovery post stem-cell transplant.5

Even the ability of stem cells to give rise to multiple cell lines can become a double-edged sword. As stem cells often mimic the characteristics of cancer cells–including changes in tumor-suppressor genes and a long life span, they may induce tumorigenesis, or cancer growth.9 ESC-derived treatments, which have been found to trigger tumor growth in animal subjects, have risk of turning cancerous because of their origin in fetal tissue, high differentiation capacity, and ability to proliferate indefi nitely.10,11 Though MSC therapies have never been found to trigger cancer growth in human patients, they should not be exempt from scrutiny; some MSC therapies have uncovered stem cells with unbalanced chromosomal arrangements and other tumor-adjacent traits.12,13

Like any novel therapy, stem cell-derived treatments should be approached cautiously. At the same time, their potential to achieve the impossible–reversing the progress of diseases once characterized by their inevitability–must also be recognized. As research on stem cells progresses, a door to the future of neurodegenerative disease treatment may open.

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