Stem Cells for Stroke
27 Apr, 2007 12:50 pm
Brain ischemia, the consequence of stroke, determines a widespread loss of different cell types in brain and thus it may benefit from exogenous stem cells replacement of lost or damaged cells. Indeed stem cells have the potential to turn into several cell types that compose the central nervous system and, in principle, may integrate into existing neural and synaptic network and re-establish cell-to-cell connections that are lost after a stroke. However they could also act through other several possible mechanisms, i.e. stimulating the protective response or neural activity in the host damaged tissue, restoring synaptic transmitter release by providing reinnervation or secreting survival promoting neurotrophic factors.
Studies focusing on restoring injured brain function through cell transplantation have shown that the infused cells can be effective in counteracting the brain damage, but the exact mechanisms by which stem cells exert their protective function remain still unclear. Besides this, the ideal conditions for their therapeutical use, such as the best source of stem cells (i.e. embryonic, foetal, adult, umbilical cord, amniotic fluid), the differentiation degree, the route of delivery, the quantity and concentration to administer, have still to be determined.
We used a particular type of stem cells that is neurosphere-derived cells. Neurospheres are heterogeneous agglomerates of cells containing both neural stem cells and immature progenitors, plus a population of more differentiated cells. We infused neurospheres in the cerebral ventricle, which is near to the lesioned area, in a murine model of cerebral ischemia in order to determine whether they could elicit a functional recovery and protection from neuronal damage.
To evaluate the functional recovery we used the ‘open field test’, a behavioural test which measures mice anxiety, motor and sensory-motor skill and explorative behaviour. We found that ischemic mice that received stem cells did not show any deficit caused by ischemia in this test and their behaviour was similar to that of a healthy mouse. In parallel with this functional recovery we also evaluated the presence of vital neurons in the ischemic area. We found that when stem cells were administered, the death of neurons was prevented.
Thus this part of the study showed that stem cells were really effective. We were then interested in understanding how these cells worked. Therefore we decided to follow the distribution of the infused cells in the brain at different time points and evaluated different parameters to identify a mechanism of action.
We found that stem cells, that were stained prior to injection with a vital fluorescent marker and were thus observable in the brain tissue, distributed rapidly all over the ischemic brain. We were very surprised by finding that these cells were scarcely visible and rapidly cleared out in the healthy brain. This finding suggested that the damaged brain favoured the survival of the stem cells and prompted us to study the communication between damaged tissue and stem cells. We thus evaluated the production of protective factors in the ischemic brain and found that the presence of stem cells was able to induce a strong production of such factors.
A further important observation was related to the role of microglia. These brain cells, that are generally believed to take part mainly in the inflammatory and toxic response, were found to be strongly activated in the ischemic brain after stem cell infusion. Actually microglia seemed to be involved in the protective effect induced by stem cells, acting through a sort of collaboration with them.
The last important finding of this study is the observation that the stem cells we used survived in the tissue for quite a short time, enough for them to exert their protective effect. This is an almost ideal condition, since undifferentiated stem cell have been questioned for their tumorigenic potential.
Our study has clearly shown that stem cells may be effective in protecting the brain following a stroke and has elucidated one possible mechanism of action. However the biology of stem cells is extremely complex and further careful studies are still needed before they can be safely used in humans.
Capone C., et al, Neurosphere-derived cells exert a neuroprotective action by changing the ischemic microenvironment, PLoS ONE, April 18, 2(4): e373