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Neuronal Precursors

Multipotent neural stem cells (NSC) have the potential to differentiate into neuronal and glial cells, and are therefore candidates for cell replacement after CNS injury. Their phenotypic fate in vivo is dependent on the engraftment site, suggesting that the environment exerts differential effects on neuronal and glial lineages.

We and others have shown that upon grafting into the adult spinal cord, NSCs remain undifferentiated or show a fate restricted to a glial lineage, indicating that the non-neurogenic adult spinal cord environment is not permissive for neuronal differentiation. The failure to obtain neuronal phenotypes after grafting NSCs into the adult spinal cord is a serious obstavle to testing therapeutic strategies directed at neuronal cell replacement. Our hypothesis has been that the adult spinal cord environment will support differentiation of lineage-restricted precursors because their intrinsic program no longer needs to initiate the commitment signals.

To identify the stage at which neuronal differentiation is inhibited, we examined the survival, differentiation, and integration of neuronal-restricted precursor (NRP) cells, derived from the embryonic spinal cord of transgenic alkaline phosphatase rats, after transplantation into the adult spinal cord. NRP cells are committed to developing into neuronal lines, having lost the ability to form glial cells.

We found that grafted NRP cells differentiate into mature neurons, survive for at least one month, appear to integrate within the host spinal cord, and extend processes in both the gray and white matter.

NRP cells in the white matter extended long branched processes, typically along the rostral-caudal axis (see high-power, inset of boxed area)

We did not observe glial differentiation from the grafted NRP cells, indicating that they retained their neuronal-restricted properties in vivo. We conclude that the adult non-neurongenic CNS environment does not support the transition of multipotent NSC to the neuronal commitemtn stage, but does allow the survival, maturation, and integration of NRP cells.

This study has been published in Experimental Neurology (Han et. al., 2002).

Mujtaba T, Han SS, Fischer I, Sandgren EP and Rao MS.  Stable expression of the alkaline phosphatase marker gene by neural cells in culture and after transplantation into the CNS using cells derived from a transgenic rat. Exp. Neurol. 2002:174:48-57

Han SS, Kang DY, Mujtaba T, Rao MS, Fischer I. Grafted lineage-restricted precursors differentiate exclusively into neurons in the adult spinal cord. Exp Neurol 2002:177:360-375

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