Math1诱导的前庭毛细胞再生的转分化过程与细胞增殖
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摘要
目的1)检验前庭膜性迷路对腺病毒载体的通透性,从而探索在外淋巴中直接给腺病毒载体对于内耳毛细胞再生研究的可行性。2)新生鼠的耳蜗上皮转染math1产生异位新生的毛细胞,本实验为了解前庭上皮细胞是否存在同样的具有分化潜能的感觉上皮。3)探索math1诱导的毛细胞样的细胞的转分化的形态学过程及分化条件、特点。
方法Ad-math1-EGFP载体的构建及其转染前庭上皮后表达的math1蛋白的检测；本实验以鼠为研究对象,以中路窝途径快速采集标本,分别建立前庭膜迷路整体培养和前庭终器培养的模型,并检验两个不同模型转染Ad-math1-EGFP载体后的效应；采用前庭终器培养的模型,使正常培养的前庭上皮感染Ad-math1-EGFP,对转染病毒后不同时间点的标本固定,部分采取冰冻切片,运用免疫组织化学进行染色后观察、采集实验数据；采用前庭终器培养,并建立高、低增殖活性的前庭感觉上皮的模型,分别将它们转染Ad-math1-EGFP,一定时间后固定、免疫组织化学染色后观察、采集实验数据；本实验以莱卡荧光显微镜、SP2或者SP5的共聚焦显微镜对标本进行观察并采集实验数据。
结果1)体外培养,膜迷路整体模型和前庭终器培养模型的首次建立。前者,尽量保持前庭膜迷路的完整性并将它们贴壁培养,培养液中给腺病毒载体,模拟在体时外淋巴给病毒；后者,去除前庭的膜性非感觉上皮并将剩余的感觉上皮贴壁培养,培养液中给腺病毒载体,模拟在体时内淋巴给病毒。2)膜迷路整体培养模式,培养液中给Ad-math1-EGFP载体,上皮细胞在非感觉上皮区出现极少量毛细胞样的细胞；前庭终器培养模式,培养液中给Ad-math1-EGFP载体,非感觉上皮区有大量的方格状细胞出现,并在此处出现大量的毛细胞样的细胞。3)异位新生的毛细胞样的细胞具有纤毛,多成簇出现,部分细胞共用一簇纤毛；细胞形态多样,呈现为多边形态、毛细胞样的形态及兼有二者特点的柱状。4)机械损伤的前庭终器,在损伤处的支持细胞增殖且在math1诱导下出现新生的毛细胞样的细胞；正常培养的前庭终器感觉上皮区极少数增殖细胞且在math1诱导下未见新生的毛细胞样的细胞；庆大霉素造模后前庭终器感觉上皮区几乎没有增殖细胞且在math1诱导下未见新生的毛细胞样的细胞5)Math1诱导的新生毛细胞样的细胞多来源于一些高增殖活性、方格状的细胞,其分化的过程中多不经历细胞的增殖,但分裂中的细胞有可能被转染并具备毛细胞的特点。
结论1)前庭膜性迷路是阻止腺病毒载体从外淋巴进入内淋巴的屏障。2)新生鼠的前庭上皮中存在一类高增殖活性的细胞,贴壁培养时,它们可以迁延、增殖,并在math1诱导下可转分化为异位的毛细胞样细胞。3)具有高增殖潜能的前体细胞转染math1后易产生毛细胞样的细胞。4)math1诱导的毛细胞样的细胞的过程是一个不依赖于细胞增殖的转分化的过程。5)毛细胞样的细胞形态多样,并具备其行使功能的基本结构静纤毛。
Objects 1) To explore the feasibility of adenovirus vectors' administration in perilymph for hair cell regeneration research, through the studies on the permeability of the vestibular membraneous labyrinth.2) New ectopic hair cell-like cells were found in the cultured neonatal rats'cochlear induced by math1gene transfer. The study tried to find the counterpart effect in the vestibular epithelia.3) To explore the conditions, the morphological transition process during the formation of hair cell-like cells induced by mathl and also the characteristics of these new cells.
Methods Ad-math1-EGFP vectors were constructed and then the efficiency of the vectors were examined; The experimental animals were neonatal rats, mice and adult mice. In vitro, the culture models of whole vestibular labyrinth and the vestibular end-organ were established respectively. The effects of the two models were tested when treated with Ad-math1-EGFP. In end-organ culture models, normal vestibular epithelia treated with Ad-math1-EGFP were fixed at different time points and part of them were sliced; Treated with Ad-math1-EGFP, vestibular epithelia with different cell proliferation capabilities were fixed at a constant time point. All these samples were analyzed by immunocytochemistry, were examined and photographed using a Leica epifluorescence microscope, SP2 or SP5 confocal microscope.
Results 1) In vitro, the successful establishment of the whole vestibular labyrinth and the vestibular end-organ culture models. The former were firstly kept the integrity of the membrane labyrinth at most and attached it to the cover-slips and then added with the adenovirus vectors to the culture media, which simulated the process of adenovirus vectors'administration in perilymph in vivo; The latter were firstly removed the non-sensory membrane labyrinth and attached the remaining sensory epithelia to the cover-slips and then were added with the vectors to the culture media, which simulated the process of adenovirus vectors' administration in endolymph in vivo 2) In whole vestibular labyrinth culture models treated with Ad-math1-EGFP, very few hair cell-like cells were found in the non-sensory region of the epithelia; in the end-organ culture models, there were some cells spreading and crawling from the sensory to non-sensory region with cubical shape. Robust hair cell-like cells were found originating from these cells in the non-sensory treated with Ad-math1-EGFP.3) These ectopic hair cell-like cells always clustered, with different cell shapes, ranging from the polygon-shape, hair-cell-shape, to the column-shape. The new cells presented with hair bundles, and sometimes the bundles were shared by two or more cells.4) In mechanical lesion vestibular epithelia, the supporting cells in lesioned epithelia had high proliferation capability, and could be differentiated into hair cell-like cells induced by mathl gene transfer; In the normal vestibular epithelia, very few supporting cells had high proliferation capability, and no hair cell-like cells were found induced by math1 gene transfer; In gentamycin treated vestibular epithelia, almost no supporting cells had high proliferation capability, and no hair cell-like cells were found induced by mathl gene transfer.5) Hair cell-like cells always originated from high proliferated cells, and were independent of cell proliferation during the process of transformation. Some cells in division were found to have the properties of hair cells.
Conclusion 1) The vestibular membraneous labyrinth is a barrier preventing the adenovirus vectors in perilymph permeating into endolymph space.2) There are some high proliferating cells in the non-sensory region that can spreading and crawling in cultured vestibular epithelia of neonatal rats or mice. And these cells can be transformed into hair cell-like cells induced by Ad-math1-EGFP.3) High proliferated progenitor cells are easy to be hair cell-like cells induced by math1 gene transfer.4) It is a transdifferentiation process that is the formation of hair cell-like cells.5) Mathl induced hair cell-like cells are of differed cell shapes and present stereocilium that makes the possibilities of the functional hair cell.
方法Ad-math1-EGFP载体的构建及其转染前庭上皮后表达的math1蛋白的检测；本实验以鼠为研究对象,以中路窝途径快速采集标本,分别建立前庭膜迷路整体培养和前庭终器培养的模型,并检验两个不同模型转染Ad-math1-EGFP载体后的效应；采用前庭终器培养的模型,使正常培养的前庭上皮感染Ad-math1-EGFP,对转染病毒后不同时间点的标本固定,部分采取冰冻切片,运用免疫组织化学进行染色后观察、采集实验数据；采用前庭终器培养,并建立高、低增殖活性的前庭感觉上皮的模型,分别将它们转染Ad-math1-EGFP,一定时间后固定、免疫组织化学染色后观察、采集实验数据；本实验以莱卡荧光显微镜、SP2或者SP5的共聚焦显微镜对标本进行观察并采集实验数据。
结果1)体外培养,膜迷路整体模型和前庭终器培养模型的首次建立。前者,尽量保持前庭膜迷路的完整性并将它们贴壁培养,培养液中给腺病毒载体,模拟在体时外淋巴给病毒；后者,去除前庭的膜性非感觉上皮并将剩余的感觉上皮贴壁培养,培养液中给腺病毒载体,模拟在体时内淋巴给病毒。2)膜迷路整体培养模式,培养液中给Ad-math1-EGFP载体,上皮细胞在非感觉上皮区出现极少量毛细胞样的细胞；前庭终器培养模式,培养液中给Ad-math1-EGFP载体,非感觉上皮区有大量的方格状细胞出现,并在此处出现大量的毛细胞样的细胞。3)异位新生的毛细胞样的细胞具有纤毛,多成簇出现,部分细胞共用一簇纤毛；细胞形态多样,呈现为多边形态、毛细胞样的形态及兼有二者特点的柱状。4)机械损伤的前庭终器,在损伤处的支持细胞增殖且在math1诱导下出现新生的毛细胞样的细胞；正常培养的前庭终器感觉上皮区极少数增殖细胞且在math1诱导下未见新生的毛细胞样的细胞；庆大霉素造模后前庭终器感觉上皮区几乎没有增殖细胞且在math1诱导下未见新生的毛细胞样的细胞5)Math1诱导的新生毛细胞样的细胞多来源于一些高增殖活性、方格状的细胞,其分化的过程中多不经历细胞的增殖,但分裂中的细胞有可能被转染并具备毛细胞的特点。
结论1)前庭膜性迷路是阻止腺病毒载体从外淋巴进入内淋巴的屏障。2)新生鼠的前庭上皮中存在一类高增殖活性的细胞,贴壁培养时,它们可以迁延、增殖,并在math1诱导下可转分化为异位的毛细胞样细胞。3)具有高增殖潜能的前体细胞转染math1后易产生毛细胞样的细胞。4)math1诱导的毛细胞样的细胞的过程是一个不依赖于细胞增殖的转分化的过程。5)毛细胞样的细胞形态多样,并具备其行使功能的基本结构静纤毛。
Objects 1) To explore the feasibility of adenovirus vectors' administration in perilymph for hair cell regeneration research, through the studies on the permeability of the vestibular membraneous labyrinth.2) New ectopic hair cell-like cells were found in the cultured neonatal rats'cochlear induced by math1gene transfer. The study tried to find the counterpart effect in the vestibular epithelia.3) To explore the conditions, the morphological transition process during the formation of hair cell-like cells induced by mathl and also the characteristics of these new cells.
Methods Ad-math1-EGFP vectors were constructed and then the efficiency of the vectors were examined; The experimental animals were neonatal rats, mice and adult mice. In vitro, the culture models of whole vestibular labyrinth and the vestibular end-organ were established respectively. The effects of the two models were tested when treated with Ad-math1-EGFP. In end-organ culture models, normal vestibular epithelia treated with Ad-math1-EGFP were fixed at different time points and part of them were sliced; Treated with Ad-math1-EGFP, vestibular epithelia with different cell proliferation capabilities were fixed at a constant time point. All these samples were analyzed by immunocytochemistry, were examined and photographed using a Leica epifluorescence microscope, SP2 or SP5 confocal microscope.
Results 1) In vitro, the successful establishment of the whole vestibular labyrinth and the vestibular end-organ culture models. The former were firstly kept the integrity of the membrane labyrinth at most and attached it to the cover-slips and then added with the adenovirus vectors to the culture media, which simulated the process of adenovirus vectors'administration in perilymph in vivo; The latter were firstly removed the non-sensory membrane labyrinth and attached the remaining sensory epithelia to the cover-slips and then were added with the vectors to the culture media, which simulated the process of adenovirus vectors' administration in endolymph in vivo 2) In whole vestibular labyrinth culture models treated with Ad-math1-EGFP, very few hair cell-like cells were found in the non-sensory region of the epithelia; in the end-organ culture models, there were some cells spreading and crawling from the sensory to non-sensory region with cubical shape. Robust hair cell-like cells were found originating from these cells in the non-sensory treated with Ad-math1-EGFP.3) These ectopic hair cell-like cells always clustered, with different cell shapes, ranging from the polygon-shape, hair-cell-shape, to the column-shape. The new cells presented with hair bundles, and sometimes the bundles were shared by two or more cells.4) In mechanical lesion vestibular epithelia, the supporting cells in lesioned epithelia had high proliferation capability, and could be differentiated into hair cell-like cells induced by mathl gene transfer; In the normal vestibular epithelia, very few supporting cells had high proliferation capability, and no hair cell-like cells were found induced by math1 gene transfer; In gentamycin treated vestibular epithelia, almost no supporting cells had high proliferation capability, and no hair cell-like cells were found induced by mathl gene transfer.5) Hair cell-like cells always originated from high proliferated cells, and were independent of cell proliferation during the process of transformation. Some cells in division were found to have the properties of hair cells.
Conclusion 1) The vestibular membraneous labyrinth is a barrier preventing the adenovirus vectors in perilymph permeating into endolymph space.2) There are some high proliferating cells in the non-sensory region that can spreading and crawling in cultured vestibular epithelia of neonatal rats or mice. And these cells can be transformed into hair cell-like cells induced by Ad-math1-EGFP.3) High proliferated progenitor cells are easy to be hair cell-like cells induced by math1 gene transfer.4) It is a transdifferentiation process that is the formation of hair cell-like cells.5) Mathl induced hair cell-like cells are of differed cell shapes and present stereocilium that makes the possibilities of the functional hair cell.
引文
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[15]Zhang Y, Zhai SQ, Shou JY, Song W, Sun JH, Guo W, Zheng GL, Hu YY, Gao WQ,2007. Isolation, growth and differentiation of hair cell progenitors from the newborn rat cochlear greater epithelial ridgele. JOURNAL OF NEUROSCIENCE METHODS 164 (2):271-279.
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[13]Oshima K, Grimm CM, Corrales CE, Senn P, Martinez Monedero R, Geleoc GS, Edge A, Holt JR, Heller S,2007. Differential Distribution of Stem Cells in the Auditory and Vestibular Organs of the Inner Ear. J Assoc Res Otolaryngol. Mar;8(1):18-31.
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[15]Zhang Y, Zhai SQ, Shou JY, Song W, Sun JH, Guo W, Zheng GL, Hu YY, Gao WQ,2007. Isolation, growth and differentiation of hair cell progenitors from the newborn rat cochlear greater epithelial ridgele. JOURNAL OF NEUROSCIENCE METHODS 164 (2):271-279.
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