Recipient Response to Stem Cells Contributes to Brain Repair in Rats

It is been known for many years that administration of a special type of stem cell, called mesenchymal stem cells, into animals after a stroke results in increased repair of the damaged areas of the brain. Specifically how this works seems to be associated with the fact that after brain damage, specific chemical signals are produced by the damaged areas of the brain that call in stem cells. This is known from animal studies, but also from human studies. In patients after a stroke, there is a large exit of stem cells from the bone marrow, from which they enter into circulation. This presumably is because the stem cells are entering the brain to cause repair. Supporting this concept are previous studies which have demonstrated that patients after a stroke who have higher number of stem cells in circulation have a better outcome as opposed to patients who have a lower number of stem cells (Dunac et al. Neurological and functional recovery in human stroke are associated with peripheral blood CD34+ cell mobilization. J Neurol. 2007 Mar;254(3):327-32). One of the main signals that the injured tissue uses to attract stem cells is stromal derived factor (SDF)-1. This signal is usually produced by bone marrow in order to retain the stem cells in the bone, when another tissue produces the same chemical but at a higher concentration, the stem cells leave the bone marrow and home to follow the chemical gradient that was produced.

A topic of significant controversy in the scientific community has been not so much the mechanisms of how stem cells go to where they are needed, but how do the stem cells mediate repair. Specifically, the argument has been whether stem cells: a) become the injured tissue. In other words, do the stem cells actually become neurons; b) produce growth factors that stimulate cells in the brain to try to repair themselves; or c) stimulate production of new blood vessels around the area of injury, so that the brain can then try to repair itself.

In a study published today from the Department of Neurology, Shimane University School of Medicine, Izumo, Japan, scientists have taken this debate one step further by asking whether the growth factors made by stem cells in response to injury are actually made by the stem cells, or whether the stem cells are "instructing" the injured tissue to make growth factors. This question has been previously difficult to answer since in most experiments the stem cells administered are of the same species as the animal receiving them.

In their publication (Wakabayashi et al. Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J Neurosci Res. 2009 Nov 2) the scientists administered three million mesenchymal stem cells generated from human bone marrow into rats that where induced to undergo a stroke by ligation of one of the arteries that feeds the brain (middle cerebral artery). As in other publications, the authors observed that rats receiving intravenous injections of human mesenchymal stem cells underwent improved functional recovery and reduced brain damage volume at 7 and 14 days after induction of the stroke when compared with rats that received placebo.

When the brains of the rats were dissected and examined for growth factor production, it was seen that the human mesenchymal stem cells were producing low levels of the human growth factor IGF-1. This was observed only on day 3 after the stroke, and only in the area on the outside of the brain damage. Surprisingly, the majority of the growth factors observed were derived from cells of rat origin. These included VEGF, EGF, and bFGF, all of which are known to be involved in brain repair.
It may be possible that there are other unknown growth factors that the human stem cells were producing that stimulated the rat brain cells to make known growth factors. This interaction between human and rat cells and how it contributes to repair still is not fully clear.

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