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.
Highlights
Degenerative and traumatic diseases of the nervous system are characterized by loss of neurons and their connections
neural stem cell (NSC) prepared for grafting were propagated as a monolayer culture in the presence of basic fibroblast growth factor (bFGF) and delivered to animals within 24 h post-bFGF withdrawal
All cells expressed the NSC marker nestin (Figure 1A), approximately 5% were immunoreactive for the neuronal precursor-specific marker PSA-NCAM, and less than 1% expressed the neuronal markers tubulin epitope J1 (TUJ1) and Microtubule-associated protein 2 (MAP2) or the astroglial marker glial fibrillary acidic protein (GFAP)
Summary
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. We grafted NSCs derived from human embryonic cord and grown in monolayer into the spinal cord of normal or injured adult rats and explored the differentiation fate and degree of structural integration of these cells as a function of time, anatomical location, and presence or absence of injury. 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.
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