October 2009 Fact Sheet

Human periventricular white matter injury (PWMI) is the predominant form of brain damage and the leading cause of life-long neurological disability from cerebral palsy in survivors of premature birth. The two major causes of PWMI are thought to be: chorioamnionitis, which can induce fetal inflammatory response, and hypoxia/ischemia (H/I), which both can cause acute degeneration of oligodendrocyte progenitors resulting in chronic myelination disturbances of neuronal axons and subsequent loss of motor control.

Recently , there has been much discussion of how cell-based therapies may used for regeneration of damaged neuronal tissue. In particular, cell based therapies may help repair/regenerate damaged neurological tissue by becoming neurons or glial cells (oligodendrocytes and astrocytes) and integrating into the neuronal network, restoring tissue by promoting activation of endogenous stem cells or by preventing tissue damage by changing body’s immune response.

Neural stem cells (NSCs) are found in the subventricular zone (SVZ) of the brain and give rise to three major cell types: neurons, astrocytes and oligodendrocytes. In development, neuroblasts from the SVZ migrate to the olfactory bulbs and a separate lineage of glioblasts migrate throughout the forebrain. While the neuroblast marker Doublecortin (Dcx) is necessary for embryonic cortical migration, it is unknown whether it is necessary for migration towards neonatal H/I lesions. Scientists are currently studying how neural stem cells respond to neo-natal hypoxia/ischemia and their potential role in repairing tissue resulting tissue damage. The researchers hypothesize that the SVZ derived stem cells redirect their migration toward brain areas injured by H/I; that SVZ NSCs expand lineage restrictions following H/I; and that Doublecortin is necessary for SVZ neuronal migration in response to H/I. This study may provide an important understanding of SVZ cell behavior in response to neonatal H/l and serve as a starting point for developing strategies to harness endogenous NSCs for repair/regeneration of damaged nerve tissue.

In addition, scientists are evaluating the role of vascular endothelial growth factor (VEGF) on neural progenitor cell proliferation and differentiation after a perinatal H/I injury. Previous research indicates although the SVZ expands in size after H/I injury, there is a shift in the production of astrocytes and oligodendrocytes. VEGF, a key mediator of tissue repair after ischemia, is rapidly induced after H/I injury and increases the specification of astrocytes rather than oligodendrocytes from bipotential glial progenitors in vitro. These researchers hypothesize that VEGF isoforms cause an aberrant shift in the proliferation and differentiation of SVZ progenitors towards astrocytic phenotypes instead of a more appropriate oligodendrocyte lineage after H/I injury. They propose to evaluate a particular isoform of VEGF that they believe will stimulate mainly oligodendrocyte production in response to a perinatal H/I injury and perhaps lead to a therapy that will stimulate endogenous neural stem cells to expand the production of oligodendrocytes for myelin repair.

Scientists are also evaluating the effects exogenous neural stem cells implanted into the SVZ of a developing brain after H/I injury. They propose to implant adult neural stem cells into the lateral ventricle or injured cortex at 24 hours and 7 days post injury. The location, cell type, and degree of differentiation of the transplanted stem cells will be analyzed 7 to 14 days post transplant. Axonal tracing studies will also be performed to begin to understand the physiologic activity of the implanted cells.

Finally, researchers are evaluating transplantation of oligodendrocyte precursors (OPCs) as a potential repair strategy in both acquired (CP) and congenital disorders of myelination. They propose to transplant genetically engineered oligodendrocyte precursors (pre OLs) into a model of congenital leukodystrophy, a condition characterized by progressive degeneration of the myelin sheath. Their previous work has demonstrated that Dlx homeobox transcription factors act as repressors of oligodendrocyte formation and maturation during embryogenesis. Cells for transplantation will be generated by using conditional Dlx2 knockout mice with loss of Dlx2 function in postnatal SVZ progenitors. The researchers hypothesize that the loss of Dlx function in the pre OLs will result in enhancement of their maturation and increased myelination of axons, and possibly a new therapeutic strategy for treatment of white matter pathology.

These studies demonstrate that, while in its infancy, cell therapies for the treatment of cerebral palsy hold great promise for a condition that has proven very difficult to prevent or cure.

October 2009 Fact Sheet