大鼠少突胶质细胞前体细胞的发育及细胞生物学特性的研究
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摘要
中枢神经系统(CNS)是由神经元和胶质细胞组成。近年来CNS中发现一类新的胶质细胞类型,依据其表达NG2硫酸软骨素多聚糖蛋白的特性,命名为少突胶质细胞前体细胞(OPCs)。一般认为OPC属于少突胶质细胞系,但是不表达成熟少突胶质细胞(OL)的蛋白标记。体外培养条件下证实OPCs也能分化为神经元和星形胶质细胞(AST),因而认为这类细胞可能是一种多潜能的干细胞。在神经元轴突髓鞘化形成前,OPCs在CNS广泛迁移。尽管OPCs可以分化成为成髓鞘的OL,但是在成熟CNS仍有大量未分化的OPCs保持这种不成熟的状态。这需要重新认识其细胞性质、与CNS其它细胞的关系、以及在前体细胞之外的功能。许多实验证实OPCs在是一种反应性胶质细胞,可能在维持神经功能和损伤修复中有作用,从而认为,OPCs可能是OL、AST之外大胶质细胞,但是尚缺乏形态学和细胞学证据。
OPCs可以与谷氨酸能和GABA能神经元形成直接的突触联系,可以接受突触前神经元信号。和神经元之间的突触结构类似,神经元-OPCs之间的突触也具有双脉冲易化现象LTP现象。但是仍不清楚突触后OPCs不能进行信息持续传递的原因。作为少突胶质系的OPCs,在缺氧缺血性脑损伤(HIBD)中细胞的变化以及在脑损伤的反应也不清楚。
因此,本文首先应用免疫组化技术研究NG2标记的OPCs在正常成年CNS的定位和表达模式。然后观察围生期OPCs的细胞生物学特点及HIBD后的变化。最后观察生后不同阶段,OPCs形态学和电生理学的特点。主要得到以下结果:
1. OPCs广泛分布于CNS各脑区。海马、白质和灰质细胞形态有差异。在灰质OPCs主要分布于非神经元层,细胞呈星形,突起向四周发散,突起长度多在10-40μm。与此对应的是,白质OPCs胞体狭长,并行的突起向胞体两极发出,与神经元轴突走向一致。突起长度多在20-50μm,比灰质细胞稍长。细胞密度在部分脑区有集中分布,但是灰质与白质无显著差异。
2. OPCs表现与神经元和AST不同的电生理特性。海马CA1区辐射层的OPCs有小的内向Na~+电流,大的外向K~+电流和延迟整流K~+电流。OPCs表现和神经元类似的电压依赖性Na~+电流,但是不能在去极化电流刺激下产生动作电位。OPCs具有比AST更高的输入阻抗(Rin),但是在静息水平对K~+仍有较大的通透性。在电流钳模式下,OPCs表现有非线性膜电位反应。而AST则仅有被动膜电位反应。在白质和海马OPCs的静息电位、膜阻抗和膜电容也不一致。
3.围生期缺氧缺血2h,海马OPCs显示更活跃的细胞膜去极化反应。细胞膜特征参数也有显著变化,包括膜电容和膜阻抗增加,而静息电位降低至超极化的水平。瞬时外向钾电流和内向整流钾电流幅度增加,而延迟整流钾电流减少。在不同的刺激模式下,OPCs表现的电流模式没有明显改变,但是电压依赖性离子通道动力学特性有显著改变,表现在:Na~+电流、瞬时外向K~+电流和尾电流激活加快,幅度增加。应用Boltzmann拟合各电压依赖离子通道的半激活电压和激活斜率因子,均表明HIBD后OPCs兴奋性增强。Na-K电导率的变化也是如此。然而AST和神经元则不表现如此显著变化。
4. OPCs持续表达于CNS生后不同发育时期。在生后7d海马和白质的OPCs即可以发出许多分支的突起,而且细胞数量在各生后时期最高。蛋白表达水平也是如此。由新生发育至成年,OPCs突起逐渐增加数量、丰富、分支复杂、长度增加。电生理特性也显示随发育而呈现瞬时外向K~+电流和延迟整流K~+电流均有增加,但是Na~+随发育成熟增加得更明显,因此Na-K电导率也随着发育成熟而增加。发育至成年,虽然去极化反应有所增加,但是Na-K电导率远小于神经元,因而OPCs仍然不能产生细胞膜动作电位反应,属于非兴奋细胞。
总之,本研究从多个方面支持认为OPCs可以作为CNS另一类大胶质细胞:⑴生后发育中突起增长、分支丰富显示形态学的复杂性;⑵膜电容和Na-K电导比率随发育成熟而增加;⑶独特的细胞生物学特点和在HIBD中的早发性反应;⑷与神经元和AST不同的形态学和电生理学特征。
The cellular composition of the vertebrate central nervous system (CNS) is traditionally thought of as consisting of neurons, astrocytes, oligodendrocytes, and microglia. Recently, a novel glial cell type has been characterized by expression of the NG2 chondroitin sulphate proteoglycan and named as oligodendrocyte precursor cell (OPC). They are thought to belong to the oligodendrocyte lineage, but do not express proteins characteristic of mature myelinating oligodendrocytes. In addition to differentiating into myelinating oligodendrocytes, OPC has been proved to be able to generate neurons and astrocytes in culture, suggesting that NG2+ OPCs in the CNS may possess stem cell-like characteristics, including multipotentiality in vitro and in vivo. NG2+ progenitors migrate throughout the developing CNS at a stage before axons have fully matured and before myelination begins. Although the majority of NG2+ cells generated during CNS development do give rise to oligodendrocytes, a significant proportion of NG2+ cells do not differentiate into myelin-forming oligodendrocytes but remain in the mature CNS with an immature phenotype. The persistence of numerous OPCs in the mature CNS has raised questions about their identities, relation to other type of CNS cells, and functions besides their progenitor role. Several lines of evidence suggest that NG2+ cells in the adult CNS represent a population of reactive glial cells. Despite of their abundance as a progenitor population and potential importance in maintenance and repair of neurological function, the developmental ontogeny of OPCs remains controversial. It was proposed that NG2 positive cells in the CNS parenchyma comprise a unique population of glia, distinct from oligodendrocytes and astrocytes. However, there was insufficient developmental evidence supporting that proposal yet.
OPCs can form direct synapses with glutamatergic and GABAergic neurons. They receive presynaptic input from neurons and respond to neurotransmitters released at synapses. As in neuron-neuron synapses, neuron-OPC synapses exhibit paired pulse facilitation and activity dependent potentiation similar to LTP in neurons, but it is not clear how activation of presynaptic neuron leads to activation of these cellular functions at different locations and developmental stages in vivo.
For this reason, we investigated the expression patterns and localization of NG2 positive OPCs in the normal adult CNS by immunohistochemistry. And then, we observed the cytological features of OPCs in perinatal hippocampus and diversities after hypoxia-ischemic brain damage. Finally, it was undertaken to determine the morphological and electrophysiological features of these cells during different postnatal developmental stages. The main results are as follows:
1. OPCs are widely distributed in several areas of adult CNS. The morphological heterogeneity of OPCs in hippocampus, grey matter and white matter of cerebral cortex was specially noted. In the grey matter, they were more densely distributed in non-neuronal layers with the classical stellate morphology. Processes of grey matter OPCs radiated in all directions from soma. The length of the processes mainly ranged from 10 to 40μm (average 25.6μm). In contrast, those in white matter had elongate cell bodies (small and round in cross section) with parallel processes extending predominantly from the two poles and passing along the nerve axis. The length of processes ranged from 20 to 50μm (average of 32.3μm), which is longer than OPCs in grey matter. Moreover, OPCs soma in white matter occupied the significantly small cell surface area than that in grey matter. No significant differences in numerical cell density were found between white matter and gray matter.
2. OPCs express instinct electrophysiological features different from astrocytes and neurons. OPCs located in the stratum radiatum region of area CA1 exhibited small Na~+ currents, large A-type and delayed rectifier K+ currents. Cells with these properties marked with intracellular Lucifer yellow had a stellate morphology, with thin, highly branched processes that extended from a small cell body. Like neurons, NG2 cells expressed voltage-gated Na~+ channels. Under physiological conditions, these Na~+ channels produced a small inflection on the rising phase of membrane potential responsed following depolarizing current injection. However, the peak amplitude of the Na~+ current was smaller than that observed in neurons under similar conditions, indicating that they expressed only a fraction of the Na~+ channels. The small number of these channels and the comparatively large K+ conductance present prevent NG2 cells from generating action potentials. Despite the higher membrane resistance of NG2 cells, their high resting membrane potential indicated that their membranes were largely permeable to K~+ at rest. Injection of positive current into NG2 cells elicited nonlinear, time-dependent changes in membrane potential unlike the passive behavior of astrocyte membranes. The predominant voltage-gated conductance responsible for these changes in membrane potential was carried by K~+. Depolarizing voltage steps from the resting potential elicited both rapidly inactivating and sustained K~+ currents. These currents consisted of conventional“A-type’’(KA) and“delayed rectifier’’type K~+ currents that are antagonized by 4-aminopyridine and tetraethylammonium, respectively. In addition to these outward K~+ currents, NG2 cells also exhibited inward K~+ currents to a variable degree. These currents were likely to result from the inwardly rectifying K~+ channels (Kir). Kir channels stabilized the membrane potential near the K~+ equilibrium potential, and maybe involved in the accumulation, buffering, or siphoning of K~+ released during neuronal activity. Other than these three electrophysiological glial profiles, a typical time dependent inactivation of symmetric K~+ tail currents following the withdrawal of voltage steps were recorded, which may participate in rest membrane potential regulation. When comparing different brain regions, the significant differences were for RMP, Rm and Cm between cells in the CA1 region of the hippocampus and the white matter of cerebral cortex.
3. OPCs in hippocampus of perinatal rats after hypoxia-ischemic brain damage for 2 hours showed more active membrane depolarization reacts than control group. Passive membrane properties for each cell were also determined with the increase of whole-cell membrane capacitance and membrane resistance, but the decrease of resting membrane potential. Both transient currents and inward rectifier currents were previously increased in OPCs of HIBD, while delayed rectifying currents decreased. To obtain a more quantitative assessment of current expression by these cells, in voltage-clamp mode a series of stimulation protocols evoked the inward and outward current in OPCs. Current traces showed qualitatively similar electrophysiological profiles in these cells, but with three notable differences: the sodium current in cells with voltage-gated Na~+ channels was significantly larger, increase of“A-type”potassium currents, and showed a larger K~+ tail current. In addition to the alternation of current amplitude, the voltage of half-maximum activation (Vmid), and the slope factor (k), which were fitted by Voltage-Charge Boltzmann equation, showed more excitable and the increase of activation of OPCs in HIBD. Na~+ to K~+ conductance ratio was also increased mainly own to the increase and activation of sodium currents. However, such changes in ion channel expression have not been obviously recorded in astrocytes and neurons in hippocampus.
4. NG2 immunopositive OPCs were continuously distributed in cerebral cortex and hippocampus during different postnatal developmental stages. These cells rapidly increase in number over the postnatal 7 days and migrate extensively to populate with abundant processes both in developing cortex and hippocampus. The morphology of OPCs exhibits extremely complex changes with the long distance primary process gradually increased the distribution number from neonatal to adult CNS. Although, in current-clamp mode, some OPCs in the early developmental stage show fluctuations in their basal membrane potential, no clear postsynaptic events were measurable. OPCs in the stratum radiatum region of area CA1 in adult (P50) hippocampus have typical voltage-gated currents exhibited large A-type and delayed rectifier K~+ currents, small inward currents which was sensitized to TTX meaning Na~+ currents, and did not fire action potentials. Membrane capacitance (Cm) of OPCs increased during postnatal development. The Na-to-K conductance ratio proved to be increased in OPCs from P0 to P50, for depolarization produced large Na~+ inward currents. These results showed that OPCs in adult were more excitable than those in perinatal stage. But low Na-to-K conductance ratio indicated that they still belonged to nonexcitable cells.
Overall, in the present study, several lines of evidence indicated that a population of NG2 immunopositive OPCs in the CNS can be considered as another separate macroglial cell type:⑴extremely morphological complex changes from neonatal to adult stage;⑵the increase of long and multiple branches processes from neonatal to adult stage;⑶the increase of membrane capacitance and Na-to-K conductance ratio during postnatal developmental stages;⑷the distinct cytological properties in perinatal hippocampus and during hypoxia-ischemic brain damage;⑸the morphological and electrophysiological features obviously different from neuron and astrocyte.
OPCs可以与谷氨酸能和GABA能神经元形成直接的突触联系,可以接受突触前神经元信号。和神经元之间的突触结构类似,神经元-OPCs之间的突触也具有双脉冲易化现象LTP现象。但是仍不清楚突触后OPCs不能进行信息持续传递的原因。作为少突胶质系的OPCs,在缺氧缺血性脑损伤(HIBD)中细胞的变化以及在脑损伤的反应也不清楚。
因此,本文首先应用免疫组化技术研究NG2标记的OPCs在正常成年CNS的定位和表达模式。然后观察围生期OPCs的细胞生物学特点及HIBD后的变化。最后观察生后不同阶段,OPCs形态学和电生理学的特点。主要得到以下结果:
1. OPCs广泛分布于CNS各脑区。海马、白质和灰质细胞形态有差异。在灰质OPCs主要分布于非神经元层,细胞呈星形,突起向四周发散,突起长度多在10-40μm。与此对应的是,白质OPCs胞体狭长,并行的突起向胞体两极发出,与神经元轴突走向一致。突起长度多在20-50μm,比灰质细胞稍长。细胞密度在部分脑区有集中分布,但是灰质与白质无显著差异。
2. OPCs表现与神经元和AST不同的电生理特性。海马CA1区辐射层的OPCs有小的内向Na~+电流,大的外向K~+电流和延迟整流K~+电流。OPCs表现和神经元类似的电压依赖性Na~+电流,但是不能在去极化电流刺激下产生动作电位。OPCs具有比AST更高的输入阻抗(Rin),但是在静息水平对K~+仍有较大的通透性。在电流钳模式下,OPCs表现有非线性膜电位反应。而AST则仅有被动膜电位反应。在白质和海马OPCs的静息电位、膜阻抗和膜电容也不一致。
3.围生期缺氧缺血2h,海马OPCs显示更活跃的细胞膜去极化反应。细胞膜特征参数也有显著变化,包括膜电容和膜阻抗增加,而静息电位降低至超极化的水平。瞬时外向钾电流和内向整流钾电流幅度增加,而延迟整流钾电流减少。在不同的刺激模式下,OPCs表现的电流模式没有明显改变,但是电压依赖性离子通道动力学特性有显著改变,表现在:Na~+电流、瞬时外向K~+电流和尾电流激活加快,幅度增加。应用Boltzmann拟合各电压依赖离子通道的半激活电压和激活斜率因子,均表明HIBD后OPCs兴奋性增强。Na-K电导率的变化也是如此。然而AST和神经元则不表现如此显著变化。
4. OPCs持续表达于CNS生后不同发育时期。在生后7d海马和白质的OPCs即可以发出许多分支的突起,而且细胞数量在各生后时期最高。蛋白表达水平也是如此。由新生发育至成年,OPCs突起逐渐增加数量、丰富、分支复杂、长度增加。电生理特性也显示随发育而呈现瞬时外向K~+电流和延迟整流K~+电流均有增加,但是Na~+随发育成熟增加得更明显,因此Na-K电导率也随着发育成熟而增加。发育至成年,虽然去极化反应有所增加,但是Na-K电导率远小于神经元,因而OPCs仍然不能产生细胞膜动作电位反应,属于非兴奋细胞。
总之,本研究从多个方面支持认为OPCs可以作为CNS另一类大胶质细胞:⑴生后发育中突起增长、分支丰富显示形态学的复杂性;⑵膜电容和Na-K电导比率随发育成熟而增加;⑶独特的细胞生物学特点和在HIBD中的早发性反应;⑷与神经元和AST不同的形态学和电生理学特征。
The cellular composition of the vertebrate central nervous system (CNS) is traditionally thought of as consisting of neurons, astrocytes, oligodendrocytes, and microglia. Recently, a novel glial cell type has been characterized by expression of the NG2 chondroitin sulphate proteoglycan and named as oligodendrocyte precursor cell (OPC). They are thought to belong to the oligodendrocyte lineage, but do not express proteins characteristic of mature myelinating oligodendrocytes. In addition to differentiating into myelinating oligodendrocytes, OPC has been proved to be able to generate neurons and astrocytes in culture, suggesting that NG2+ OPCs in the CNS may possess stem cell-like characteristics, including multipotentiality in vitro and in vivo. NG2+ progenitors migrate throughout the developing CNS at a stage before axons have fully matured and before myelination begins. Although the majority of NG2+ cells generated during CNS development do give rise to oligodendrocytes, a significant proportion of NG2+ cells do not differentiate into myelin-forming oligodendrocytes but remain in the mature CNS with an immature phenotype. The persistence of numerous OPCs in the mature CNS has raised questions about their identities, relation to other type of CNS cells, and functions besides their progenitor role. Several lines of evidence suggest that NG2+ cells in the adult CNS represent a population of reactive glial cells. Despite of their abundance as a progenitor population and potential importance in maintenance and repair of neurological function, the developmental ontogeny of OPCs remains controversial. It was proposed that NG2 positive cells in the CNS parenchyma comprise a unique population of glia, distinct from oligodendrocytes and astrocytes. However, there was insufficient developmental evidence supporting that proposal yet.
OPCs can form direct synapses with glutamatergic and GABAergic neurons. They receive presynaptic input from neurons and respond to neurotransmitters released at synapses. As in neuron-neuron synapses, neuron-OPC synapses exhibit paired pulse facilitation and activity dependent potentiation similar to LTP in neurons, but it is not clear how activation of presynaptic neuron leads to activation of these cellular functions at different locations and developmental stages in vivo.
For this reason, we investigated the expression patterns and localization of NG2 positive OPCs in the normal adult CNS by immunohistochemistry. And then, we observed the cytological features of OPCs in perinatal hippocampus and diversities after hypoxia-ischemic brain damage. Finally, it was undertaken to determine the morphological and electrophysiological features of these cells during different postnatal developmental stages. The main results are as follows:
1. OPCs are widely distributed in several areas of adult CNS. The morphological heterogeneity of OPCs in hippocampus, grey matter and white matter of cerebral cortex was specially noted. In the grey matter, they were more densely distributed in non-neuronal layers with the classical stellate morphology. Processes of grey matter OPCs radiated in all directions from soma. The length of the processes mainly ranged from 10 to 40μm (average 25.6μm). In contrast, those in white matter had elongate cell bodies (small and round in cross section) with parallel processes extending predominantly from the two poles and passing along the nerve axis. The length of processes ranged from 20 to 50μm (average of 32.3μm), which is longer than OPCs in grey matter. Moreover, OPCs soma in white matter occupied the significantly small cell surface area than that in grey matter. No significant differences in numerical cell density were found between white matter and gray matter.
2. OPCs express instinct electrophysiological features different from astrocytes and neurons. OPCs located in the stratum radiatum region of area CA1 exhibited small Na~+ currents, large A-type and delayed rectifier K+ currents. Cells with these properties marked with intracellular Lucifer yellow had a stellate morphology, with thin, highly branched processes that extended from a small cell body. Like neurons, NG2 cells expressed voltage-gated Na~+ channels. Under physiological conditions, these Na~+ channels produced a small inflection on the rising phase of membrane potential responsed following depolarizing current injection. However, the peak amplitude of the Na~+ current was smaller than that observed in neurons under similar conditions, indicating that they expressed only a fraction of the Na~+ channels. The small number of these channels and the comparatively large K+ conductance present prevent NG2 cells from generating action potentials. Despite the higher membrane resistance of NG2 cells, their high resting membrane potential indicated that their membranes were largely permeable to K~+ at rest. Injection of positive current into NG2 cells elicited nonlinear, time-dependent changes in membrane potential unlike the passive behavior of astrocyte membranes. The predominant voltage-gated conductance responsible for these changes in membrane potential was carried by K~+. Depolarizing voltage steps from the resting potential elicited both rapidly inactivating and sustained K~+ currents. These currents consisted of conventional“A-type’’(KA) and“delayed rectifier’’type K~+ currents that are antagonized by 4-aminopyridine and tetraethylammonium, respectively. In addition to these outward K~+ currents, NG2 cells also exhibited inward K~+ currents to a variable degree. These currents were likely to result from the inwardly rectifying K~+ channels (Kir). Kir channels stabilized the membrane potential near the K~+ equilibrium potential, and maybe involved in the accumulation, buffering, or siphoning of K~+ released during neuronal activity. Other than these three electrophysiological glial profiles, a typical time dependent inactivation of symmetric K~+ tail currents following the withdrawal of voltage steps were recorded, which may participate in rest membrane potential regulation. When comparing different brain regions, the significant differences were for RMP, Rm and Cm between cells in the CA1 region of the hippocampus and the white matter of cerebral cortex.
3. OPCs in hippocampus of perinatal rats after hypoxia-ischemic brain damage for 2 hours showed more active membrane depolarization reacts than control group. Passive membrane properties for each cell were also determined with the increase of whole-cell membrane capacitance and membrane resistance, but the decrease of resting membrane potential. Both transient currents and inward rectifier currents were previously increased in OPCs of HIBD, while delayed rectifying currents decreased. To obtain a more quantitative assessment of current expression by these cells, in voltage-clamp mode a series of stimulation protocols evoked the inward and outward current in OPCs. Current traces showed qualitatively similar electrophysiological profiles in these cells, but with three notable differences: the sodium current in cells with voltage-gated Na~+ channels was significantly larger, increase of“A-type”potassium currents, and showed a larger K~+ tail current. In addition to the alternation of current amplitude, the voltage of half-maximum activation (Vmid), and the slope factor (k), which were fitted by Voltage-Charge Boltzmann equation, showed more excitable and the increase of activation of OPCs in HIBD. Na~+ to K~+ conductance ratio was also increased mainly own to the increase and activation of sodium currents. However, such changes in ion channel expression have not been obviously recorded in astrocytes and neurons in hippocampus.
4. NG2 immunopositive OPCs were continuously distributed in cerebral cortex and hippocampus during different postnatal developmental stages. These cells rapidly increase in number over the postnatal 7 days and migrate extensively to populate with abundant processes both in developing cortex and hippocampus. The morphology of OPCs exhibits extremely complex changes with the long distance primary process gradually increased the distribution number from neonatal to adult CNS. Although, in current-clamp mode, some OPCs in the early developmental stage show fluctuations in their basal membrane potential, no clear postsynaptic events were measurable. OPCs in the stratum radiatum region of area CA1 in adult (P50) hippocampus have typical voltage-gated currents exhibited large A-type and delayed rectifier K~+ currents, small inward currents which was sensitized to TTX meaning Na~+ currents, and did not fire action potentials. Membrane capacitance (Cm) of OPCs increased during postnatal development. The Na-to-K conductance ratio proved to be increased in OPCs from P0 to P50, for depolarization produced large Na~+ inward currents. These results showed that OPCs in adult were more excitable than those in perinatal stage. But low Na-to-K conductance ratio indicated that they still belonged to nonexcitable cells.
Overall, in the present study, several lines of evidence indicated that a population of NG2 immunopositive OPCs in the CNS can be considered as another separate macroglial cell type:⑴extremely morphological complex changes from neonatal to adult stage;⑵the increase of long and multiple branches processes from neonatal to adult stage;⑶the increase of membrane capacitance and Na-to-K conductance ratio during postnatal developmental stages;⑷the distinct cytological properties in perinatal hippocampus and during hypoxia-ischemic brain damage;⑸the morphological and electrophysiological features obviously different from neuron and astrocyte.
引文
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