Abstract
Recent studies have indicated that the choice of lineage of neural progenitor cells is determined, at least in part, by environmental factors, such as neurotrophic factors. Despite extensive studies using exogenous neurotrophic factors, the effect of endogenous neurotrophic factors on the differentiation of progenitor cells remains obscure. Here we show that embryonic spinal cord derived-progenitor cells express both ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) mRNA before differentiation. BDNF gene expression significantly decreases with their differentiation into the specific lineage, whereas CNTF gene expression significantly increases. The temporal pattern of neurotrophic factor gene expression in progenitor cells is similar to that of the spinal cord during postnatal development. Approximately 50% of spinal progenitor cells differentiated into astrocytes. To determine the effect of endogenous CNTF on their differentiation, we neutralized endogenous CNTF by administration of its polyclonal antibody. Neutralization of endogenous CNTF inhibited the differentiation of progenitor cells into astrocytes, but did not affect the numbers of neurons or oligodendrocytes. Furthermore, to mimic the profile of neurotrophic factors in the spinal cord during embryonic development, we applied BDNF or neurotrophin (NT)-3 exogenously in combination with the anti-CNTF antibody. The exogenous application of BDNF or NT-3 promoted the differentiation of these cells into neurons or oligodendrocytes, respectively. These findings suggest that endogenous CNTF and exogenous BDNF and NT-3 play roles in the differentiation of embryonic spinal cord derived progenitor cells into astrocytes, neurons and oligodendrocytes, respectively.
Highlights
Neural stem/progenitor cells are an ideal source of tissue for neural transplantation, since these cells can be expanded in vitro, maintained in an undifferentiated state and retain the capacity to differentiate into neurons, astrocytes and oligodendrocytes [1,2,3]
To determine how neurotrophic factor gene expression is regulated in the spinal cord during normal development, we examined the neurotrophic factor gene expression profiles of developing spinal cord between Embryonic Days 14 (E14) and P17 by RNase protection assay
A high level of NT-3 gene expression, a moderate level of ciliary neurotrophic factor (CNTF) and a low level of Brain-derived neurotrophic factor (BDNF) were observed in E14 spinal cord, but the bands for nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF) or NT-4 were undetectable (Fig. 1A)
Summary
Neural stem/progenitor cells are an ideal source of tissue for neural transplantation, since these cells can be expanded in vitro, maintained in an undifferentiated state and retain the capacity to differentiate into neurons, astrocytes and oligodendrocytes [1,2,3]. The exogenous addition of ciliary neurotrophic factor (CNTF) and subsequent gp130-signal activation promotes the differentiation of astrocytes from embryonic hippocampus, cortex and spinal cord derived progenitor cells [11,12,13,14,15,16]. Neurotrophin-3 (NT-3) induces neuronal differentiation from embryonic cortex and hippocampus derived progenitor cells [18,19] Despite these extensive studies using the exogenous application of neurotrophic factors, little is known about the effect of endogenous neurotrophic factors on the differentiation of progenitor cells. We sought to determine the extent to which differentiation of spinal progenitor cells is altered by manipulation of endogenous as well as exogenous neurotrophic factors in vitro. A better understanding of the control mechanism of spinal progenitor cell’s fate should enhance efforts to develop effective transplantation strategies aimed at restoring functional connectivity in the injured spinal cord
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