Date Published: February 13, 2007
Publisher: Public Library of Science
Author(s): Jun Yan, Leyan Xu, Annie M Welsh, Glen Hatfield, Thomas Hazel, Karl Johe, Vassilis E Koliatsos, Sally Temple
Abstract: BackgroundEffective treatments for degenerative and traumatic diseases of the nervous system are not currently available. The support or replacement of injured neurons with neural grafts, already an established approach in experimental therapeutics, has been recently invigorated with the addition of neural and embryonic stem-derived precursors as inexhaustible, self-propagating alternatives to fetal tissues. The adult spinal cord, i.e., the site of common devastating injuries and motor neuron disease, has been an especially challenging target for stem cell therapies. In most cases, neural stem cell (NSC) transplants have shown either poor differentiation or a preferential choice of glial lineages.Methods and FindingsIn the present investigation, we grafted NSCs from human fetal spinal cord grown in monolayer into the lumbar cord of normal or injured adult nude rats and observed large-scale differentiation of these cells into neurons that formed axons and synapses and established extensive contacts with host motor neurons. Spinal cord microenvironment appeared to influence fate choice, with centrally located cells taking on a predominant neuronal path, and cells located under the pia membrane persisting as NSCs or presenting with astrocytic phenotypes. Slightly fewer than one-tenth of grafted neurons differentiated into oligodendrocytes. The presence of lesions increased the frequency of astrocytic phenotypes in the white matter.ConclusionsNSC grafts can show substantial neuronal differentiation in the normal and injured adult spinal cord with good potential of integration into host neural circuits. In view of recent similar findings from other laboratories, the extent of neuronal differentiation observed here disputes the notion of a spinal cord that is constitutively unfavorable to neuronal repair. Restoration of spinal cord circuitry in traumatic and degenerative diseases may be more realistic than previously thought, although major challenges remain, especially with respect to the establishment of neuromuscular connections.
Partial Text: Degenerative and traumatic diseases of the nervous system are characterized by loss of neurons and their connections. Effective treatments for these conditions are presently unavailable. In the field of experimental therapeutics two major approaches have been taken: prevention of cell death with compounds that interfere with decision-making steps in cell death pathways and the replacement or support of degenerating neurons with neural grafts [1,2]. Neural stem cells (NSCs) are a promising alternative to fetal tissues for cell therapies, primarily due to their self-renewal and pluripotentiality [3,4]. The use of human-derived NSCs has the additional advantage of yielding translational information that is relevant to clinical therapeutics.