The Final Frontier: Stem Cells and Neural Repair Following Stroke

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By: Denisha Puvitharan

Affiliations: Queen’s University, 4th year student in Life Sciences (Specialization in Drug Development and Human Toxicology)

Supervisor: Dr. Cindi M. Morshead, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto

In a world where space probes are sending back breathtakingly accurate photos of the surface of Pluto, there seems to be no end in sight for the leaps and bounds of technology. Once thought to be the final frontier of human exploration, scientists have now sent probes as far as 18.8 billion kilometers into deep space, yet the 86 billion neurons in the human brain still proves to be a mystery.1,2

For much of the 20th century, the brain was believed to be the most developed part of the human body, specialized to the point that it was capable of controlling actions as large as gross movement of limbs to tasks as fine as iris dilation. However, this mastery came at a price. It was believed at this time that the brain was so specialized that it had lost the basic function of self-repair that was present in the rest of the body. This meant that unlike skin, which heals after a cut, the brain had no method of rescuing itself or creating new neurons, presenting a dark future for those with especially damaging neural conditions. Fortunately, this is not the case. Following the creation of theories of neuroplasticity and the discovery of adult stem cells here at the University of Toronto in the early 60s by McCulloch and Till, doors were blown wide open to the possibility of curing debilitating neural conditions such as Parkinson’s, Alzheimer’s, complications due to stroke and many other devastating illnesses.3

Stroke currently represents the third largest cause of death in Canada, killing approximately 14 000 people a year in our nation alone.4 With one stroke occurring every ten minutes in a now aging population and over 315 000 Canadians living with the long-term effects of stroke, it has become increasingly relevant to not only stop the spread of damage during strokes, but also to rescue cognitive function.5,6 Currently, one of the only available drug treatments for stroke are tissue plasminogen activators which work to actively degrade blood clots present in ischemic strokes, but not in hemorrhagic strokes.7 Other limitations of this treatment is that it must be applied within four and a half hours from stroke onset for any results to be seen and that it only addresses the neuroprotective aspect of stroke treatment, not neural repair.7

This is where stem cells enter the picture. Following the isolation of a pool of neural stem cells present in the subventricular zone of the lateral ventricles by Reynolds and Weiss in 1992, the possibility of repairing these once thought to be permanent damages has become far more plausible.8 Though stem cells were once thought to be useful as a cure-all treatment, scientists are still trying to outline their limitations and work towards medically relevant applications. Neural stem cells and their progeny, collectively known as neural precursor cells (NPCs) present two possible avenues of this much needed neural healing, through transplantation and through endogenous activation. Due to the ethical concerns and immunological complications surrounding the transplantation of stem cells, the focus of my summer research project was to try and enhance endogenous production of NPCs in the mammalian brain. When the brain is capable of such feats, why not try to capitalize on such abilities? As indicated by previous research, NPCs travel to sites of injury in order to aid in neural repair, but this alone is not enough to heal the damage caused by stroke.9 Nevertheless, there is still hope for this method of healing. Previous research indicates that these NPC pools can be targeted and enhanced through the use of small molecules such as Cyclosporin A (CsA) and Metformin.10,11 Our lab has also shown that when enhanced with CsA, these NPCs are capable of rescuing behavioural function that was previously lost due to stroke in mice.12

But what does that mean for patients suffering from stroke related complications and other brain conditions? It means that there may be hope for these brains to heal themselves through simple amplification of pre-existing mechanisms of brain repair. This presents the possibility for a treatment that could restore neural and behavioural function to the hundreds of thousands of patients living with post-stroke complications. Though it may be years before this treatment is prescribed, it still represents a novel method of patient healing capable of rescuing cognition. Perhaps the final frontier of human science is not light years away as previously believed, but rather in our own heads, resting in the power to help our brains heal themselves.

References:

  1. Azevedo AC, et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled‐up primate brain. Journal of Comparative Neurology. 2009 [Cited 2015 Aug 13]; 513.5:532-541.
  2. Landau E. NASA confirms Voyager 1 probe has left the solar system – CNN.com [Internet]. CNN. Cable News Network; 2013 [cited 2015 Aug 13]. Retrieved from: http://www.cnn.com/2013/09/12/tech/innovation/voyager-solar-system/
  3. Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 1963 [Cited 2015 Aug 13]; 197:452-454.
  4. The 10 leading causes of death, 2011 [Internet]. Statistics Canada. Government of Canada; 2014 [cited 2015]. Retrieved from: http://www.statcan.gc.ca/pub/82-625-x/2014001/article/11896-eng.htm
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  7. Stroke medications [Internet]. Heart and Stroke Foundation. 2011 [cited 2015 Aug 12]. Retrieved from: http://www.heartandstroke.com/site/c.ikiqlcmwjte/b.3484223/k.71d9/stroke___medications.htm
  8. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992 [Cited 2015 Aug 16]; 255.5052:1707-1710.
  9. Sachewsky N, Morshead CM. Adult Stem Cells and Their Role in Endogenous Tissue Repair. Emerging Technology Platforms for Stem Cells. 2009 [Cited 2015 Aug 13]; 1: 87-109.
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  11. Dadwal P, et al. Activating Endogenous Neural Precursor Cells Using Metformin Leads to Neural Repair and Functional Recovery in a Model of Childhood Brain Injury. Stem Cell Reports. 2015 [Cited 2015 Aug 20]; 5.2: 166-173.
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