A very interesting study published in September 2008, looked at the effects that human stem cells have in stroke-affected mice. The general expectations were that stem cells would help replenish the dead brain cells (i.e. regenerate healthy tissue), thus resulting in a recovery from the stroke. But Nature works in mysterious ways…

This new research by Hirokazu Ohtaki et. al. [1], confirmed the positive effects of injecting stem cells to the brains of mice that had suffered a stroke: neuron damage was reduced by 60% albeit not simply by replenishing damaged tissue as expected. But before moving on to the unexpected results, let’s first have a very (very) brief primer on the pathophysiology of strokes^*.

Stroke is a condition of a rapidly deteriorating brain functioning due to a reduced blood availability. This can happen either because of a problem in the blood supplying arteries (e.g. thrombosis in the carotid arteries, which drive blood to the brain) or because of a hemorrhage (where blood loss occurs because of raptured blood vessels). The former is called ischemia and is of interest to us for this post.

When the blood supply is significantly reduced, after only a minute or two the brain tissue stops functioning properly because of lack of oxygen. When a few hours have passed, irreversible damage occurs in brain tissue: due to oxygen and glucose starvation, all energy-dependant processes required for the cells to survive are halted.

Also (and importantly for appreciating the study), the first signs of brain injury elicit a response by the immune system. The now panicked, overreacting immune system goes on to attack and damage healthy brain tissue thus worsening the condition! There is evidence that the resulting inflammation plays a significant role in the progressions of the stroke (for a review see [2]). Therefore, calming down the immune system could help alleviate the brain cell damage.

OK, back to the study: what did the authors do? They induced a stroke on lab mice by blocking their carotid arteries. The next day, they injected human stem cells^** directly into the hippocampus in their brains, expecting to see a regeneration of healthy tissue by these young and as-yet-unspecialised cells. Yet this is what happened (taken from the original paper):

The hMSCs [human stem cells] persisted for <7 days, but they down-regulated >10% of the ischemia-induced genes, most of which were involved in inflammatory and immune responses. The hMSCs also up-regulated three mouse genes, including the neuroprotective gene Ym1 that is expressed by activated microglia/macrophages.

What does this mean? It means that the stem cells did not directly help in generating new healthy tissue as expected. Instead, they helped in regulating the genes that have been affected by the ischemic stroke, calming down more than 10% of the overreacting inflammatory and immune system agents (thus significantly reducing brain cell deaths).

Stem cells also increased regulation of three genes that activate the microglia and brain macrophages of the immune system. Errr, so? you may ask. Well, microglia hold the leading role in detecting damaged neurons in the central nervous system as well as express neurotrophins that promote the development and normal function of neurons [3]. However, microglia are also activated and accumulated within the brain tissue right after an ischemic stroke, thus leading to inflammatory injury as described above. Messy stuff you say? That’s right…

Nevertheless, the authors conclude that:

[t]he observed beneficial effects of hMSCs were largely explained by their modulation of inflammatory and immune responses, apparently by alternative activation of microglia and/or macrophages.

This is a very active area of research and if any more evidence is needed to show that stem cell research can have unimaginable results in our understanding, diagnosing, and treating a vast array of conditions, please let me know what that evidence might be…

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Footnotes:

1. * Any biologist, medical doctor, or simply more adequately educated in this subject reader, feel free to correct my oversimplified description or add more information [↩]
2. ** Why human and not mice stem cells? Because human stem cells are much easier to isolate and cultivate than mice stem cells [↩]

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References:

1. Hirokazu Ohtaki, Joni H. Ylostalo, Jessica E. Foraker, Andrew P. Robinson, Roxanne L. Reger, Seiji Shioda, Darwin J. Prockop, "Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses," Proceedings of the National Academy of Sciences,Sep 2008, vol. 105 no. 38, pp. 14638-14643. [↩]
2. Qing Wang, Xian Nan Tang, Midori A. Yenari, "The Inflammatory Response in Stroke," Journal of Neuroimmunology, 2007 March, vol. 184 no. 1-2, pp. 53–68. [↩]
3. S. Elkabes, EM. DiCicco-Bloom, IB. Black , "Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function," Journal of Neuroscience, vol 16, pp. 2508-2521 [↩]