体外共培养诱导嗅球神经前体细胞分化为功能性外周神经元
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摘要
目的听觉神经系统损伤后的修复是临床亟待解决的问题之一。近几年的研究寄希望于将外源性多潜能细胞移植到内耳并替代受损的听感觉上皮和听神经元的功能。尽管不同来源的移植细胞在被移植动物的内耳可以部分存活,我们对它们的功能却一无所知。我们尝试在体外模拟内耳微环境,检测嗅球来源神经前体细胞在体外分化进程中能否发育为较成熟的神经元,拥有一定的功能。
方法培养嗅球神经前体细胞取自孕14-16d胚胎大鼠,有限稀释法传代并免疫荧光染色鉴定神经干细胞及其分化潜能。将嗅球来源神经前体细胞与新生大鼠耳蜗细胞悬液共同培养,应用免疫组织化学、膜片钳技术、RT-PCR、钙测定等技术检测嗅球来源NPCs在体外分化细胞的形态学、分子生物学、生理学特性,并与听感觉神经元——螺旋神经节细胞进行比较。
结果虽然经诱导分化得到的神经元样细胞、毛细胞样细胞的比例仍然不够高,但是这些细胞已显示对外周神经元标志物、毛细胞标志物免疫组织化学染色阳性。RT-PCR提示外周感觉神经原特异的蛋白与转录因子的mRNA的表达。在共培养诱导分化条件下,细胞逐渐发育,并能在外加刺激下形成较成熟的动作电位。分化两周的神经元样细胞可以形成有一定功能的离子型的谷氨酸受体。
结论本试验说明嗅球来源NPCs可以在体外转化为功能性的谷氨酸能外周神经元,可以成为耳聋细胞移植治疗的合适的供体细胞。
Hearing impairment is one of the most common disabilities in the modern era, affecting 250 million people worldwide. Hearing depends largely on hair cells(HCs) and their associated spiral ganglion neurons (SGNs), and defects in these cells produce permanent deafness. The cochlear sensory epithelium and its associated neural components do not, in mammals, regenerate or repair naturally following severe injury. As functional recovery by innate regeneration is thus not possible, the development of therapeutic techniques that were able to replace damaged cells and thus to restore inner ear function would represent a considerable advance in the treatment of deafness.
Recent studies have revealed the potential of cell transplantation for the treatment of inner ear diseases. When implanted in the inner ear, embryonic tissue, neural stem cells (NSCs) and ESCs can survive, migrate toward afferent neurons, and generate neurite projections. However, although morphological and immunohistochemical analyses show that the implanted cells in these studies resemble neurons, no physiological information has been obtained that would identify these cells as functional neurons. In addition, it is not clear whether the cochlea of adults is able to provide the necessary extracellular microenvironment needed to drive these neuron-like cells through the developmental stages that would be required to generate functional afferent neurons and hair cells. Since the ultimate goal of this group of studies is to restore hearing in patients, it is of key importance to assess the function of implanted cells.
Aim: The objective of the present study was to induce the differentiation of NPCs towards functional auditory-neuron-like cells, using an established coculture model in vitro to mimic, as closely as possible, the developing cochlear environment.
Methods: We undertook to direct the differentiation of NPCs derived from the olfactory bulb in vitro, using established co-culture models.
Result: Differentiated NPCs were immunolabeled for peripheral neuron markers. RT-PCR assays also indicated expression of peripheral neuron marker transcripts. Over a period of four weeks in culture, differentiated neuron-like cells showed a number of electrophysiological properties and gradually developed into mature cells compared with SGNs. After two weeks, the newly differentiated neurons also expressed functional ionotropic glutamate receptors.
Conclusion: These results demonstrated that NPCs from the olfactory bulb can differentiate into functional auditory neuron-like cells, and thus may potentially provide a source of replacement neurons for repair of the deafened mammalian cochlea.
方法培养嗅球神经前体细胞取自孕14-16d胚胎大鼠,有限稀释法传代并免疫荧光染色鉴定神经干细胞及其分化潜能。将嗅球来源神经前体细胞与新生大鼠耳蜗细胞悬液共同培养,应用免疫组织化学、膜片钳技术、RT-PCR、钙测定等技术检测嗅球来源NPCs在体外分化细胞的形态学、分子生物学、生理学特性,并与听感觉神经元——螺旋神经节细胞进行比较。
结果虽然经诱导分化得到的神经元样细胞、毛细胞样细胞的比例仍然不够高,但是这些细胞已显示对外周神经元标志物、毛细胞标志物免疫组织化学染色阳性。RT-PCR提示外周感觉神经原特异的蛋白与转录因子的mRNA的表达。在共培养诱导分化条件下,细胞逐渐发育,并能在外加刺激下形成较成熟的动作电位。分化两周的神经元样细胞可以形成有一定功能的离子型的谷氨酸受体。
结论本试验说明嗅球来源NPCs可以在体外转化为功能性的谷氨酸能外周神经元,可以成为耳聋细胞移植治疗的合适的供体细胞。
Hearing impairment is one of the most common disabilities in the modern era, affecting 250 million people worldwide. Hearing depends largely on hair cells(HCs) and their associated spiral ganglion neurons (SGNs), and defects in these cells produce permanent deafness. The cochlear sensory epithelium and its associated neural components do not, in mammals, regenerate or repair naturally following severe injury. As functional recovery by innate regeneration is thus not possible, the development of therapeutic techniques that were able to replace damaged cells and thus to restore inner ear function would represent a considerable advance in the treatment of deafness.
Recent studies have revealed the potential of cell transplantation for the treatment of inner ear diseases. When implanted in the inner ear, embryonic tissue, neural stem cells (NSCs) and ESCs can survive, migrate toward afferent neurons, and generate neurite projections. However, although morphological and immunohistochemical analyses show that the implanted cells in these studies resemble neurons, no physiological information has been obtained that would identify these cells as functional neurons. In addition, it is not clear whether the cochlea of adults is able to provide the necessary extracellular microenvironment needed to drive these neuron-like cells through the developmental stages that would be required to generate functional afferent neurons and hair cells. Since the ultimate goal of this group of studies is to restore hearing in patients, it is of key importance to assess the function of implanted cells.
Aim: The objective of the present study was to induce the differentiation of NPCs towards functional auditory-neuron-like cells, using an established coculture model in vitro to mimic, as closely as possible, the developing cochlear environment.
Methods: We undertook to direct the differentiation of NPCs derived from the olfactory bulb in vitro, using established co-culture models.
Result: Differentiated NPCs were immunolabeled for peripheral neuron markers. RT-PCR assays also indicated expression of peripheral neuron marker transcripts. Over a period of four weeks in culture, differentiated neuron-like cells showed a number of electrophysiological properties and gradually developed into mature cells compared with SGNs. After two weeks, the newly differentiated neurons also expressed functional ionotropic glutamate receptors.
Conclusion: These results demonstrated that NPCs from the olfactory bulb can differentiate into functional auditory neuron-like cells, and thus may potentially provide a source of replacement neurons for repair of the deafened mammalian cochlea.
引文
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