POTENTIAL ROLE FOR STEM CELLS IN THE TREATMENT OF CEREBRAL PALSY
February 2007

Partly due to the significant increase in survival of the very premature infants in the last decades, cerebral palsy of perinatal origin is not decreasing and has even been shown to increase in some Western countries. This condition has devastating consequences for the individual and for society. Multiple factors can cause injury to the developing brain leading to cerebral palsy. Many preconceptional, prenatal and perinatal factors (endocrine imbalances, genetic factors, oxidative damage, and maternal infection among others) are known to be associated with brain injury. Perinatal hypoxia/ischemia, a disruption of blood and oxygen delivery to the brain, is a primary cause of brain injury in the newborn. To date there are no effective means to repair the brain once damage has occurred. Moreover, since many of these insults occur in utero, prevention may prove difficult, and regenerative strategies may be a better alternative to reduce the damage to the brain.

Neural stem/progenitor cells (NSPs) have been recently identified in the mammalian central nervous system, including humans, at all stages of life. Defined as self-renewing, primordial cells with the capacity to give rise to all cell lineages in all regions of the nervous system, NSPs are found in the germinal zone in the brain of the embryo and fetus where they participate in central nervous system formation. Cells equally “stem like” in their potential have been identified at later stages in life from a variety of regions in the brain. It seems that ongoing lifelong self-repair and plasticity are a fundamental developmental program set in place during early stages of brain development.

In adult stroke models, newly generated neural cells that survive and mature have been reported in different affected areas of the brain. Recently, several studies on the neonatal brain reveal that it contains multipotent neural stem cells and precursors with the potential to replace multiple classes of brain cells after damage.

In a neonatal mouse model of hypoxia- ischemia Plane and colleagues reported that most of the new neurons being generated fail to integrate and survive long term. These findings suggest that although new neurons are generated in the developing brain, long term survival of such newly generated neurons is not supported.

Felling and colleagues also provide evidence of an NSP response to a perinatal hypoxia-ischemia insult. These data represent the first evidence that self-renewing, multipotential precursors initiate a regenerative response to perinatal hypoxia-ischemia, giving rise to all cell types in the brain. It is encouraging that, Contrary to Plane’s findings, the same group of investigators reported that the newly generated neurons reach maturation and that a subset of them is retained for at least five months. (data in press).

Many questions and concerns remain unanswered in regard to the role of NSPs on the normal human brain development and repair. Because of the limited replacement of brain cells that occurs naturally, it is likely that the number of resident NSPs available is insufficient to repopulate the brain fully after an injury. Strategies to expand the regenerative potential of the NSPs of the individual or exogenous stem cell transplantation may be necessary. The success of any attempted repair will depend on the severity of the insult, the ability of the environment where the NSPs live to sustain them, and the ability of these cells to migrate to the site of injury, mature and survive. Concerns regarding the possibility of tumor development from NSPs arise from some reports and cannot be ignored. Much needs to be learned about stem cells before they can be use to improve the outcome of babies with brain injury.

1. Plane JM, Liu R, Wang TW, Silverstein FS, Parent JM. Neonatal hypoxic-ischemic injury increases forebrain subventricular zone neurogenesis in the mouse. Neurobiol Dis. 2004;16:585–595

2. Felling RJ, Snyder MJ, Romanko MJ, et al. Neural stem/progenitor cells participate in the regenerative response to perinatal hypoxia/ischemia. J Neurosci. 2006;26:4359–4369