小鼠听囊细胞的培养、自然分化、移植与小鼠听觉剥夺后蜗神经核可塑性的研究
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摘要
第一部分小鼠听囊细胞的培养和自然分化
目的:探讨从小鼠的胚胎中分离、培养、诱导听囊细胞增殖与自然分化的可能性。方法:从孕9.5-10.5天C57B6/L小鼠胚胎的听囊组织分离出听囊细胞,采用无血清培养,进行体外培养、扩增,并通过免疫荧光化学染色(nestin)进行鉴定。取传至第4代听囊细胞,接种于盖玻片上。添加血清培养基,培养15天后行免疫荧光检测和RT-PCR检测。观察听囊细胞的体外分化特点。
结果:采用无血清培养法自听囊中成功地培养出听囊细胞球,利用听囊细胞球进行听囊细胞的纯化与传代,免疫荧光检测示:听囊细胞的nestin表达阳性,RT-PCR对BMP7,NESTIN,P27kip1,SOX2的检测证实其具有内耳前体细胞的特点。在含血清培养基培养15天后,免疫荧光检测证实所获听囊细胞可以在体外被诱导分化为MyosinⅦa和Synaptophysin阳性的细胞。结论:小鼠听囊中的细胞具有普通干细胞的自我复制,自我更新的特点,可分化为内耳毛细胞和神经元。
第二部分小鼠听囊与听囊细胞的耳蜗移植
目的:通过对移植入成年小鼠耳蜗内的听囊组织与听囊细胞的分布及分化能力的短期观察,对听囊和听囊细胞的在体内的存活、增殖能力进行分析。方法:采用9.5-10.5dpc听囊组织和Hoechst33342标记的听囊细胞,经耳蜗第二转处移植入正常成年C5786/L小鼠耳蜗中。术后1天时观察听囊组织在耳蜗内的存活与分布情况,1周时观察移植的听囊和听囊细胞在耳蜗的存活与分布情况。观察时用4%多聚甲醛磷酸盐心脏灌注小鼠,取下并固定颞骨,冰冻组织切片。结果:听囊细胞移植入正常成年C5786/L小鼠耳蜗7天后,主要分布于蜗管内基底膜表面,并可以迁移到鼓阶和前庭阶中。听囊组织1天后可以存活在鼓阶中,1周后观察到出现增殖。结论:听囊细胞短期内可以在耳蜗基底膜表面存活,可以迁移到鼓阶和前庭阶中。听囊组织短期内可以在耳蜗中存活、增殖。
第三部分听觉剥夺小鼠蜗神经核的形态学改变
目的:为进一步研究听觉剥夺对听觉中枢神经核团的远期影响,本实验通过切除小鼠双侧耳蜗剥夺听觉,研究术后4个月时听觉脑干中蜗神经核内神经元发生的形态学改变。方法:采用20只听力正常成年小鼠,随机分为对照组和试验组,每组10只。实验组小鼠在解剖显微镜下,用显微手术器械切除鼓室后壁,损毁耳蜗。术后进行ABR测试评估听力。术后继续饲养小鼠。4个月后处死小鼠,取脑组织进行脑干连续切片行尼氏染色和银染,研究蜗神经核的腹侧前核、腹侧后核、背侧核、章鱼样细胞核群的形态变化。结果:术后4个月实验组蜗神经核神经元数量较对照组明显减少,章鱼样细胞群具有特征性的形态学变化,细胞面积减小,细胞数目减少,细胞核团的总体积也明显低于其他核团。结论:双侧听觉剥夺四个月能够导致小鼠的蜗神经核体积减小,神经元数量减少。
Loss of hair cells and spiral ganglion cells which involve sensorineural hearing impairment, is irreversible, and is usually followed with changes in auditory center. Just only for the characteristic of the mentioned above, stem-cell-implantation is the most hopeful methods commended in therapy of sensorineural hearing impairment. Up to now, some researches have showed that stem cells possess potentials to differentiate into hair-cell-like cells or neurons after cochlear implantation, however, people little knows about the corresponding auditory center. So, to study cells implantation in hearing loss causing the effect of auditory center, we attempt to cultivate cells from otocyst and further explore the effect of auditory deprivation in morphology along with the feasibility in implanting otocyst cells and otocyst by cochlear operation.
PartⅠ: Culture and Induced Differentiation of Otocyst Cells from Mouse
Objective: To study the feasibility of isolation and culture of stem cells from the otocyst of mouse embryos, and characterize the differentiation of Cells from otocyt. Methods: 22 pregnant adult mice were enrolled with study. At 9.5-10.5 days post coitum, otocysts were dissected out successfully from embryos, and then were dissociated in Hank's Buffered Salt Solution (HBSS). After digestion, cells from otocyst were cultured in serum free medium with BFGF and EGF in vitro. After formed otosphere, cells were purified in the form of otosphere and then passaged with neurosphere assay. Immunocytochemistry (ICC) and RT-PCR were taken. To explore the ability of differentiation, cells from otosphere were cultured with serum medium and examed with ICC and RT-PCR after 15days in serum medium. Antibodies against nestin, NSE, myosinVIIa and synaptophysin were used being the marker of stem cell and inner ear cells and neurons. Results: Otocyst was formed by invagination of the embryonic ectodermal tissue near the hindbrain. 22 Otocysts were obtained successfully from embryonic mouse. Otospheres were fromed after 3 days cultured in serum free medium in vitro. Results of ICC and RT-PCR suggest nestin was expressed in cells from otoshperes. After 15 days culture on adherent in the medium containing serum, cells were differentiated into cells with positive marker expression of myosinVIIa and NSE and synaptophysin. Some transcription factor including BMP7, Nestin, SOX2, PAX6, myosinVIIa and jagged-1 were presented with RT-PCR. Conclution: Cells with self-renewed capacity and potential multi-differentiation exist in the otocyst of mouse. Cells of otocyst show the general charactization of common stem cells. They can especially differentiate into hair cells and neuron in vitro.
PartⅡ: Transplantation of Otocyst and Cells from Otocyt into the Cochlear of Mouse
Objective: To study the characters of migration and survival of Cells from otocyt s in cochlear and explore the ability of differentiation for inner ear cell and neurons in vivo. Methods: After labeled with Hoechst 33342, cells from otocyst were transplanted into the cochlear of healthy adult mouse. Meanwhile, tissues of otocyst were transplanted into the cochlear of normal adult mouse. At one week post-grafting, after perfusion in heart with 4% paraformaldehyde in 0.01 M phosphate-buffered saline, The temporal bones were collected and immersed in the 4% paraformaldehyde in 0.01 M phosphate-buffered saline (PBS) at pH 7.4 for 4 h at 4℃. Cryostat sections 3μm thick were made, and the mid-modiolus sections were used for histological analysis. Antibody aginst myosinVIIa and synaptophysin were used to test the differentiation of Cells from otocyt s invivo. Results: At one week post-grafting, Cells from otocyt were localized on the surface of basilar membrane of cochlear, and migrate into scala tympani and scala vestibuli. For the tissues of otocyst, survival and proliferation were also found in scala tympani. Conclusion: Cells from otocyt can survive on the surface of base membrane of cochlear and migrate into scala tympani and scala vestibuli,. The tissues of otocyst were also found in scala tympani, and can proliferate. These cells have the possibility of treatment of deafness.
PartⅢ: Morphometric Study of the Cochlear Nucleus of Mouse Model of Cochlear Ablation
Objective: To study the morphological features of the auditory centre induced by the mouse model of auditory deprived. Methods: 20 BABL/c mice were used in the present study. Mice were checked for normal hearing by auditory brainstem response (ABR) prior to the study, were divided into experimental group and control group at random. Afer the lateral wall of the dorsal and mastoid bulla mouse was removed, the cochlea was destoried in experimental group. The two groups mice were also checked by auditory brainstem response after operation. The animals were allowed to survive 4 months. The brain stems were continuously sectioned. Histological sections of the cochlear nucleus were evaluated with serial sections and several strains for neurons, and fibers. The volume of cochlear nucleus and number of neurons in cochlear nucleus were evaluated four months later. Results: We establish a stable auditory deprived mouse model with cochlea ablation. A decrease in volume of the CN and a loss of neurons in the CN were observed. Conclusion: The cochlea ablation was an excellent method for establishing the auditory deprived animal model. The degeneration of cochlea nucleus can be induced by auditory deprived even for a long time in adult mouse.
目的:探讨从小鼠的胚胎中分离、培养、诱导听囊细胞增殖与自然分化的可能性。方法:从孕9.5-10.5天C57B6/L小鼠胚胎的听囊组织分离出听囊细胞,采用无血清培养,进行体外培养、扩增,并通过免疫荧光化学染色(nestin)进行鉴定。取传至第4代听囊细胞,接种于盖玻片上。添加血清培养基,培养15天后行免疫荧光检测和RT-PCR检测。观察听囊细胞的体外分化特点。
结果:采用无血清培养法自听囊中成功地培养出听囊细胞球,利用听囊细胞球进行听囊细胞的纯化与传代,免疫荧光检测示:听囊细胞的nestin表达阳性,RT-PCR对BMP7,NESTIN,P27kip1,SOX2的检测证实其具有内耳前体细胞的特点。在含血清培养基培养15天后,免疫荧光检测证实所获听囊细胞可以在体外被诱导分化为MyosinⅦa和Synaptophysin阳性的细胞。结论:小鼠听囊中的细胞具有普通干细胞的自我复制,自我更新的特点,可分化为内耳毛细胞和神经元。
第二部分小鼠听囊与听囊细胞的耳蜗移植
目的:通过对移植入成年小鼠耳蜗内的听囊组织与听囊细胞的分布及分化能力的短期观察,对听囊和听囊细胞的在体内的存活、增殖能力进行分析。方法:采用9.5-10.5dpc听囊组织和Hoechst33342标记的听囊细胞,经耳蜗第二转处移植入正常成年C5786/L小鼠耳蜗中。术后1天时观察听囊组织在耳蜗内的存活与分布情况,1周时观察移植的听囊和听囊细胞在耳蜗的存活与分布情况。观察时用4%多聚甲醛磷酸盐心脏灌注小鼠,取下并固定颞骨,冰冻组织切片。结果:听囊细胞移植入正常成年C5786/L小鼠耳蜗7天后,主要分布于蜗管内基底膜表面,并可以迁移到鼓阶和前庭阶中。听囊组织1天后可以存活在鼓阶中,1周后观察到出现增殖。结论:听囊细胞短期内可以在耳蜗基底膜表面存活,可以迁移到鼓阶和前庭阶中。听囊组织短期内可以在耳蜗中存活、增殖。
第三部分听觉剥夺小鼠蜗神经核的形态学改变
目的:为进一步研究听觉剥夺对听觉中枢神经核团的远期影响,本实验通过切除小鼠双侧耳蜗剥夺听觉,研究术后4个月时听觉脑干中蜗神经核内神经元发生的形态学改变。方法:采用20只听力正常成年小鼠,随机分为对照组和试验组,每组10只。实验组小鼠在解剖显微镜下,用显微手术器械切除鼓室后壁,损毁耳蜗。术后进行ABR测试评估听力。术后继续饲养小鼠。4个月后处死小鼠,取脑组织进行脑干连续切片行尼氏染色和银染,研究蜗神经核的腹侧前核、腹侧后核、背侧核、章鱼样细胞核群的形态变化。结果:术后4个月实验组蜗神经核神经元数量较对照组明显减少,章鱼样细胞群具有特征性的形态学变化,细胞面积减小,细胞数目减少,细胞核团的总体积也明显低于其他核团。结论:双侧听觉剥夺四个月能够导致小鼠的蜗神经核体积减小,神经元数量减少。
Loss of hair cells and spiral ganglion cells which involve sensorineural hearing impairment, is irreversible, and is usually followed with changes in auditory center. Just only for the characteristic of the mentioned above, stem-cell-implantation is the most hopeful methods commended in therapy of sensorineural hearing impairment. Up to now, some researches have showed that stem cells possess potentials to differentiate into hair-cell-like cells or neurons after cochlear implantation, however, people little knows about the corresponding auditory center. So, to study cells implantation in hearing loss causing the effect of auditory center, we attempt to cultivate cells from otocyst and further explore the effect of auditory deprivation in morphology along with the feasibility in implanting otocyst cells and otocyst by cochlear operation.
PartⅠ: Culture and Induced Differentiation of Otocyst Cells from Mouse
Objective: To study the feasibility of isolation and culture of stem cells from the otocyst of mouse embryos, and characterize the differentiation of Cells from otocyt. Methods: 22 pregnant adult mice were enrolled with study. At 9.5-10.5 days post coitum, otocysts were dissected out successfully from embryos, and then were dissociated in Hank's Buffered Salt Solution (HBSS). After digestion, cells from otocyst were cultured in serum free medium with BFGF and EGF in vitro. After formed otosphere, cells were purified in the form of otosphere and then passaged with neurosphere assay. Immunocytochemistry (ICC) and RT-PCR were taken. To explore the ability of differentiation, cells from otosphere were cultured with serum medium and examed with ICC and RT-PCR after 15days in serum medium. Antibodies against nestin, NSE, myosinVIIa and synaptophysin were used being the marker of stem cell and inner ear cells and neurons. Results: Otocyst was formed by invagination of the embryonic ectodermal tissue near the hindbrain. 22 Otocysts were obtained successfully from embryonic mouse. Otospheres were fromed after 3 days cultured in serum free medium in vitro. Results of ICC and RT-PCR suggest nestin was expressed in cells from otoshperes. After 15 days culture on adherent in the medium containing serum, cells were differentiated into cells with positive marker expression of myosinVIIa and NSE and synaptophysin. Some transcription factor including BMP7, Nestin, SOX2, PAX6, myosinVIIa and jagged-1 were presented with RT-PCR. Conclution: Cells with self-renewed capacity and potential multi-differentiation exist in the otocyst of mouse. Cells of otocyst show the general charactization of common stem cells. They can especially differentiate into hair cells and neuron in vitro.
PartⅡ: Transplantation of Otocyst and Cells from Otocyt into the Cochlear of Mouse
Objective: To study the characters of migration and survival of Cells from otocyt s in cochlear and explore the ability of differentiation for inner ear cell and neurons in vivo. Methods: After labeled with Hoechst 33342, cells from otocyst were transplanted into the cochlear of healthy adult mouse. Meanwhile, tissues of otocyst were transplanted into the cochlear of normal adult mouse. At one week post-grafting, after perfusion in heart with 4% paraformaldehyde in 0.01 M phosphate-buffered saline, The temporal bones were collected and immersed in the 4% paraformaldehyde in 0.01 M phosphate-buffered saline (PBS) at pH 7.4 for 4 h at 4℃. Cryostat sections 3μm thick were made, and the mid-modiolus sections were used for histological analysis. Antibody aginst myosinVIIa and synaptophysin were used to test the differentiation of Cells from otocyt s invivo. Results: At one week post-grafting, Cells from otocyt were localized on the surface of basilar membrane of cochlear, and migrate into scala tympani and scala vestibuli. For the tissues of otocyst, survival and proliferation were also found in scala tympani. Conclusion: Cells from otocyt can survive on the surface of base membrane of cochlear and migrate into scala tympani and scala vestibuli,. The tissues of otocyst were also found in scala tympani, and can proliferate. These cells have the possibility of treatment of deafness.
PartⅢ: Morphometric Study of the Cochlear Nucleus of Mouse Model of Cochlear Ablation
Objective: To study the morphological features of the auditory centre induced by the mouse model of auditory deprived. Methods: 20 BABL/c mice were used in the present study. Mice were checked for normal hearing by auditory brainstem response (ABR) prior to the study, were divided into experimental group and control group at random. Afer the lateral wall of the dorsal and mastoid bulla mouse was removed, the cochlea was destoried in experimental group. The two groups mice were also checked by auditory brainstem response after operation. The animals were allowed to survive 4 months. The brain stems were continuously sectioned. Histological sections of the cochlear nucleus were evaluated with serial sections and several strains for neurons, and fibers. The volume of cochlear nucleus and number of neurons in cochlear nucleus were evaluated four months later. Results: We establish a stable auditory deprived mouse model with cochlea ablation. A decrease in volume of the CN and a loss of neurons in the CN were observed. Conclusion: The cochlea ablation was an excellent method for establishing the auditory deprived animal model. The degeneration of cochlea nucleus can be induced by auditory deprived even for a long time in adult mouse.
引文
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1. Li H, Roblin G, Liu H, Heller S. Generation of hair cells by stepwise differentiation of embryonic stem cells. ProcNatl Acad Sci U S A. 2003,11 ;100(23): 13495-13500.
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10. Davies E, Gladstone HB, Williams H, et al. A model for long-term intracochlear administration of pharmacologic agents. Am J Otology1994.15:757-761.
11. Petri Olivius , Leonid Alexandrov , Joe Miller.A llografted fetal dorsal root ganglion neuronal survival in the guinea pig cochlea. Brain Research 979(2003) 1-6.
12. Mark A. Parker, Deborah A. Neural Stem Cells Injected into the Sound-Damaged Cochlea Migrate Throughout the Cochlea and Express Markers of Hair Cells, Supporting Cells, and Spiral Ganglion Cells. Hear Res.2007; 232(1-2): 29-43.
1.田永胜,张萌,陈晓巍等.小鼠听觉剥夺动物模型的建立.基础与临床医学杂志.2008,6,618-612
2.Basta D,Tzschentke B,Ernst A.Noise-induced cell death in the mouse medial geniculate body and primary auditory cortex.Neurosci Letters,2005,381:199-204.
3.BRAAK E;BRAAK H,Silver staining method for demonstrating Lewy bodies in Parkinson's disease and argyrophilic oligodendrocytes in multiple system atrophy.J ournal of Neuroscience Methods,1999,87,1,111-115.
4.James F.Willott,Lori Seegers Bross.Morphology of the octopus cell area of the cochlear nucleus in young and aging C57BL/6J and CBA/J mice.The Journal of Comparative Neurology,1990,300,1,61 - 81.
5.Durham D,Park DL,Girod DA.Central nervous system plasticity during hair cell loss and regeneration.Hear Res,2004,147:145-159.
6.Mostafapour SP,Cochran SL,Del Puerto NM,Rubel EW.Patterns of cell death in mouse anteroventral cochlear nucleus neurons after unilateral cochlea removal.J Comp Neurol,2000,426:561-571.
7.Kim J,Morest DK,Bohne BA.Degeneration of axons in the brainstem of the chinchilla after auditory overstimulation.Hear Res,1997,103:169-191.
8. George Paxinos, George Paxinos. The Mouse Brain in Stereotaxic Coordinates, second edition. ACADEMIC PRESS, 2001.
9. K.K. Osen, Cytoarchitecture of the cochlear nuclei in the cat, J.Comp. Neurol.1969,136:453-484.
10. E.S.C. Kane, Octopus cells in the cochlear nucleus of the cat:heterotypic synapses upon homeotypic neurons, Int. J. Neurosci. 1973,5: 251-279.
11. J.C. Adams, Single unit studies on the dorsal and intermediateacoustic striae, J.Comp. Neurol. 1976,170: 97-106.
12. E.M. Rouiller, D.K. Ryugo, Intracellular marking of physiologically characterized cells in the ventral cochlear nucleus of the cat, J. Comp. Neurol.1984,225:167-186.
13. L.A. Ritz, W.E. Brownell, Single unit analysis of the posteroventral cochlear nucleus of the decerebrate cat, Neuroscience 1982,7:1995-2010.
14. Snyder RL, Leake PA.Topography of spiral ganglion projections to cochlear nucleus during postnatal development in cats. J Comp Neurol.1997,28;293-311.
15. Frisina RD, Walton JP. Age-related structural and functional changes in the cochlear nucleus. Hear Res. 2006;216-217:216-23.
16. Kazee AM, Han LY, Spongr VP, Walton JP, et al. Synaptic loss in the central nucleus of the inferior colliculus correlates with sensorineural hearing loss in the C57BL/6 mouse model of presbycusis. Hear Res. 1995;89(1-2): 109-20.
1.Li H,Roblin G,Liu H,Heller S.Generation of hair cells by stepwise differentiation of embryonic stem cells.Proc Natl Acad Sci U S A.2003,11;100(23):13495-13500.
2.Rivolta MN,Li H,Heller S.Generation of inner ear cell types from embryonic stem cells.Methods Mol Biol.2006;330:71-92.
3.Li,H.,Liu,H.,Heller,S.Pluripotent stem cells from the adult mouse inner ear.Nat.Med.9,1293-1299.
4.Malgrange B,Belachew S,Thiry M,et all.Proliferative generation of mammalian auditory hair cells in culture.Mechanisms of Development,2002,112(1-2):79-88.
5.Savary E,Hugnot JP,Chassigneux Y,et al.Distinct population of hair cell progenitors can be isolated from the postnatal mouse cochlea using side population analysis.2007,25(2):332-9.
6.Senn P,Oshima K,Teo D,Robust.Postmortem Survival of Murine Vestibular and Cochlear Stem Cells.J Assoc Res Otolaryngol.2007,8(2):194-204.
7.Yerukhimovich MV,Bai L,Chen DH,et al.Identification and characterization of mouse cochlear stem cells.Dev Neurosci.2007,29(3):251-260.
8.Lou X,Zhang Y,Yuan C.Multipotent stem cells from the young rat inner ear.Neurosci Lett.2007,6;416(1):28-33.
9.Jeon SJ,Oshima K,Heller S,et al.Bone marrow mesenchymal stem cells are progenitors in vitro for inner ear hair cells.Mol Cell Neurosci.2007,34(1):59-68.
10.Doyle KL,Kazda A,Hort Y,et al.Differentiation of adult mouse olfactory precursor cells into hair cells in vitro.Stem Cells.2007,25(3):621-627.
11.Kojima K,Tamura S,Nishida AT,et al.Generation of inner ear hair cell immunophenotypes from neurospheres obtained from fetal rat central nervous system in vitro.Acta Otolaryngol Suppl.2004,(551):26-30.
12.Coleman B,Fallon JB,Pettingill LN,et al.Auditory hair cell explant co-cultures promote the differentiation of stem cells into bipolar neurons.Exp Cell Res.2007,15;313(2):232-243.
13.Kageyama R.Nakanishi S.Helix-loop-helix factors in growth and diferentiation of the vertebrate nervous system.Curr Opin Genet Dev.1997,7:659-665.
14.Jan-Jan Liu,June Ho Shin,Krzysztof L,et al.Stem Cell Therapy for Hearing Loss: Mathl Over expression in VOT-E36 Cells. Otology Neurotology.2006,27:414-421.
15. Hasson T, Heintzelman MB, Santos-Sacchi J,et al. Expression in cochlea and retina of myosin Vila, the gene product defective in Usher syndrome type 1B. Proc Natl Acad Sci USA .1995,10;9815-9819.
16. Ninkina NN, Stevens GE, Wood JN, et al. A novel Brn3-like POU transcription factor expressed in Generation of hair cell types from CNS 29 subsets of rat sensory and spinal cord neurons. Nucleic Acids Res 1993; 21:3175_3182.
17. Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cell derived from adult marrow 1 Nature, 2002,418(6893): 412-491.
18. Naito Y, Nakamura T, Iguchi F, et al. Transplantation of autologous mesenchymal stem cells into the cochlea of the chinchilla. Neuroreport,2004,15(1): 1-4.
19. ParkerMA, Cotanche DA1 The potential use of stem cells for cochlear repairlAudiol Neurootol, 2004, 9 (2): 722-801.
20. Yoshida T, Hakuba N, Morizane I, Fujita K, et al. Hematopoietic stem cells prevent hair cell death after transient cochlear ischemia through paracrine effects. Neuroscience. 2007;145(3):923-30.
21. Ito J, Kojima K, Kawaguchi S. Survival of neural stem cells in the cochlear.Acta Otolaryngol, 2001,121 (2): 1402-1421.
22. Tateya I,Nakagawa T, Iguchi F, et al. Fate of neural stem cells graftedinto injured inner ears of mice Neuroreport, 2003, 14 (13) :16772-16811.
23. Sakamoto T, Nakagawa T, Endo T, Kim TS, Iguchi F, Naito Y, Sasai Y,Ito J.Fates of mouse embryonic stem cells transplanted into the inner ears of adult mice and embryonic chickens. Acta Otolaryngol Suppl. 2004 Mar;(551):48-52.
24. Li H, Corrales CE, Edge A, et all.Stem cells as therapy for hearing loss.TrendsMolMed, 2004,10 (7): 3092-3151.
25. Miller JM, ChiDH,O'Keeffe LJ, et all Neurotrophins can enhance spirral ganglion cell survival after inner hair cell loss1 Int J DevNeurosci, 1997, 15(425): 6312-6431.
26. Hu Z, Ulfendahl M, Olivius NP. NGF stimulates extensive neurite outgrowth from implanted dorsal root ganglion neurons following transplantation into the adult rat inner ear. Neurobiol Dis. 2005 Feb;18(1):184-92.
27. Iguchi F, Nakagawa T, Tateya I, Kim TS, Endo T, Taniguchi Z, Naito Y, Ito J. Trophic support of mouse inner ear by neural stem cell transplantation.Neuro Report 2003; 14:77-80.
28. Tamura T, Nakagawa T, Iguchi F et al. Transplantation of neural stem cells into the modiolus of mouse cochleae injured by cisplatin. Acta Otolaryngol Suppl 2004;551:65-68.
29. Okano T, Nakagawa T, Endo T, Kim TS, Engraftment of embryonic stem cell-derived neurons into the cochlear modiolus.Neuroreport. 2005 Nov 28;16(17): 1919-22.
30. Regala C, Duan M, Zou J, et al. Xenografted fetal dorsal root ganglion,embryonic stem cell and adult neural stem cell survival following implantation into the adult vestibulocochlear nerve. Exp Neurol.2005;193:326-33.
31. Hakuba N, Hata R, Morizane I, et al. Neural stem cells suppress the hearing threshold shift caused by cochlear ischemia. Neuroreport. 2005 28;16:1545-9.
32. Coleman B, Hardman J, Coco A, et al. Fate of embryonic stem cells transplanted into the deafened mammalian cochlea. Cell Transplant.2006;15:369-80.
1.Dexter R.F.Irvine.Auditory cortical plasticity:Does it provide evidence for cognitive processing in the auditory cortex? Hearing Research,2007,229,1-2,158-170.
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17. Ruttiger L, Panford-Walsh R, Schimmang T.BDNF mRNA expression and protein localization are changed in age-related hearing loss..Neurobiol Aging.2007;28:586-601
2. Li H, Liu H, Heller S. Pluripotent stem cells from the adult mouse inner ear. Nat Med. 2003; 9(10):1293-9.Ruben, R.J.,Development of the inner ear of the mouse: a radioautographic study of terminal mitosis. Acta Otolaryngol. 1967. 220,1-44.
3. Zhai S, Shi L, Wang BE, et al. Isolation and culture of hair cell progenitors from postnatal rat cochleae. J Neurobiol. 2005 ;65(3):282-93.
4. Malgrange B, Belachew S, Thiry M, et all. Proliferative generation of mammalian auditory hair cells in culture. Mechanisms of Development,2002,112(1-2):79-88.
5. Lou X, Zhang Y, Yuan C. Multipotent stem cells from the young rat inner ear. Neurosci Lett. 2007,6;416(1):28-33.
6. Savary E, Hugnot JP, Chassigneux Y, et al. Distinct population of hair cell progenitors can be isolated from the postnatal mouse cochlea using side population analysis.2007,25(2):332-9.
7. Yerukhimovich MV, Bai L, Chen DH, et al. Identification and characterization of mouse cochlear stem cells. Dev Neurosci.2007,29(3):251-260.
8. Barald, K.F., Lindberg, K.H., Hardiman, K., Kavka, A.I., Lewis, J.E.,Victor, J.C., Gardner, C.A., Poniatowski, A., Immortalized cell lines from embryonic avian and murine otocysts: tools for molecular studies of the developing inner ear. Int. J. Dev.Neurosci. 1997,15, 523 — 540.
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11. Tatsunori Sakamoto, Juichi Ito, Raj K. Ladher. Hair cell differentiation becomes tissue specific by E9.5 in mouse inner ear. NeuroReport 18:841-844.
12. Kojima K, Murata M, Nishio T, et al. Survival of fetal rat otocyst cells grafted into the damaged inner ear. Acta Otolaryngol Suppl.2004;(551):53-5.
13. Kim TS, Kojima K, Nishida AT, Tashiro K.Expression of calretinin by fetal otocyst cells after transplantation into damaged rat utricle explants. Acta Otolaryngol Suppl.2004;(551):34-8.
1. Li H, Roblin G, Liu H, Heller S. Generation of hair cells by stepwise differentiation of embryonic stem cells. ProcNatl Acad Sci U S A. 2003,11 ;100(23): 13495-13500.
1. Rivolta MN, Li H, Heller S. Generation of inner ear cell types from embryonic stem cells. Methods Mol Biol. 2006;330:71-92.
2. Barald, K.F., Lindberg, K.H., Hardiman, K., Kavka, A.I., Lewis, J.E., Victor, J.C.,Gardner, C.A., Poniatowski, A., Immortalized cell lines from embryonic avian and murine otocysts: tools for molecular studies of the developing inner ear. Int. J.Dev.Neurosci. 1997, 15,523-540.
3. Kalinec, K, Kalinec, G, Boukhvalova, M., Kachar, B., Establishment and characterization of conditionallyimmortaliz ed organ of Corti. Cell Biol. Int. 1999, 23,175-184.
4. Rivolta, M.N, Grix, N., Lawlor, P, Ashmore, J.F, Jagger, D.J.,Holley, M.C., Auditory hair cell precursors immortalized from the mammalian inner ear. Proc. R. Soc. Lond. B 1998,265,1595-1603.
5. Rivolta, M.N.,Rivolta, M.N., Holley, M.C., Cell lines in inner ear research.J. Neurobiol.2002,53,306-318.
6. Ruben, R.J., Development of the inner ear of the mouse: a radioautographic study of terminal mitoses. Acta Otolaryngol. 1967. 220, 1-44.
7. Represa, J., Frenz, D.A., Van De Water, T.R.. Genetic patterning of embryonic inner ear development. Acta Otolaryngol. 2000; 120,5-10.
8. Morsli, H., Choo, D., Ryan, A., Johnson, R.,, et al. Development of the mouse inner ear and origin of its sensoryorgans.J. Neurosci. 1998;18, 3327-3335.
9. Masashi Ozeki, Lijie Duan, Yuki Hamajima.Establishment and characterization of rat progenitor hair cell lines.Hearing Research,2003;179,1-2, 43-52.
10. Using the Neurosphere Assay to Quantify Neural Stem Cells In Vivo. Curr Pharm Biotechnol. 2007 ;8(3):141-5. Gregory P. Marshall II1, Brent A. Reynolds2 , Eric D.Laywell.
11. Lillien, L., Raphael, H., BMP and FGF regulate the development of EGF responsive neural progenitor cells. Development 2000.127, 4993 - 5005.
12. Viti, J., Feathers, A., Phillips, J., Lillien, L., Epidermal growth factor receptors control competence to interpret leukemia inhibitory factor as an astrocyte inducer in developing cortex. J. Neurosci. 2003.23, 3385 - 3393.
13. V. Graham, J. Khudyakov, P. Ellis , L. Pevny, SOX2 functions to maintain neural progenitor identity, Neuron,2003; 39. 749-765.
14. Robert Hugues Duparc, Mohamed Abdouh, Jocelyn David,etal. Pax6 controls the proliferation rate of neuroepithelial progenitors from the mouse optic vesicle.Developmental Biology.2007; 301,374 - 387.
15. Seung-Ha Oh, Randy Johnson, Doris K. Wu. Differential Expression of Bone Morphogenetic Proteins in the Developing Vestibular and Auditory Sensory Organs.J. Neurosci. 16: 6463-6475.
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17. Lowenheim H, Furness DN, Kil J, et al.Gene disruption of p27(Kipl) allows cell proliferation in the postnatal and adult organ of corti. Proc Natl Acad Sci U S A.1999,30;96(7):4084-8.
18. Brooker R, Hozumi K, Lewis J.Notch ligands with contrasting functions: Jaggedl and Deltal in the mouse inner ear. Development. 2006 Apr;133(7):1277-86.
1.Ruben,R.J.,Development of the inner ear of the mouse:a radioautographic study of terminal mitosis.Acta Otolaryngol.1967.220,1-44..
2.Chen Y,Qiu J,Chen F,Liu S..Migration of neural precursor cells derived from olfactory bulb in cochlear nucleus exposed to an augmented acoustic environment.Hear Res.2007,228(1-2);3-10.
3.Ruben,R.J.,Development of the inner ear of the mouse:a radioautographic study of terminal mitosis.Acta Otolaryngol.1967.220,1-44.
4.Tatsunori Sakamoto,Juichi Ito,Raj K.Ladher.Hair cell differentiation becomes tissue specific by E9.5 in mouse inner ear.NeuroReport 18:841- 844.
5.Tamura T,Nakagawa T,Iguchi F,et al.Transplantation of neural stem cells into the modiolus of mouse cochleae injured by cisplatin.Acta Otolaryngol Suppl.2004;551:65-68.
6.Corrales CE,Pan L,Li H,et al.Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear bunk:growth of processes into the organ of Corti.J Neurobiol.2006;66(13):1489-500.
7.Hu Z,Ulfendahl M,Olivius NP.Central migration of neuronal tissue and embryonic stem cells following transplantation along the adult auditory nerve.Brain Res.2004;1026(1):68-73.
8.Iguchi F,Nakagawa T,Tateya I,et al.Surgical Techniques for Cell Transplantation into the Mouse Cochlea.Acta Otolaryngol.2004;(551):43-7.
9. KAKIGI A, TAKEDAT. Effect of artificial endolymph injection into the cochlear duct on the endocochlear potential. Hearing Research, 1998; 16, 1-2:113-118.
10. Davies E, Gladstone HB, Williams H, et al. A model for long-term intracochlear administration of pharmacologic agents. Am J Otology1994.15:757-761.
11. Petri Olivius , Leonid Alexandrov , Joe Miller.A llografted fetal dorsal root ganglion neuronal survival in the guinea pig cochlea. Brain Research 979(2003) 1-6.
12. Mark A. Parker, Deborah A. Neural Stem Cells Injected into the Sound-Damaged Cochlea Migrate Throughout the Cochlea and Express Markers of Hair Cells, Supporting Cells, and Spiral Ganglion Cells. Hear Res.2007; 232(1-2): 29-43.
1.田永胜,张萌,陈晓巍等.小鼠听觉剥夺动物模型的建立.基础与临床医学杂志.2008,6,618-612
2.Basta D,Tzschentke B,Ernst A.Noise-induced cell death in the mouse medial geniculate body and primary auditory cortex.Neurosci Letters,2005,381:199-204.
3.BRAAK E;BRAAK H,Silver staining method for demonstrating Lewy bodies in Parkinson's disease and argyrophilic oligodendrocytes in multiple system atrophy.J ournal of Neuroscience Methods,1999,87,1,111-115.
4.James F.Willott,Lori Seegers Bross.Morphology of the octopus cell area of the cochlear nucleus in young and aging C57BL/6J and CBA/J mice.The Journal of Comparative Neurology,1990,300,1,61 - 81.
5.Durham D,Park DL,Girod DA.Central nervous system plasticity during hair cell loss and regeneration.Hear Res,2004,147:145-159.
6.Mostafapour SP,Cochran SL,Del Puerto NM,Rubel EW.Patterns of cell death in mouse anteroventral cochlear nucleus neurons after unilateral cochlea removal.J Comp Neurol,2000,426:561-571.
7.Kim J,Morest DK,Bohne BA.Degeneration of axons in the brainstem of the chinchilla after auditory overstimulation.Hear Res,1997,103:169-191.
8. George Paxinos, George Paxinos. The Mouse Brain in Stereotaxic Coordinates, second edition. ACADEMIC PRESS, 2001.
9. K.K. Osen, Cytoarchitecture of the cochlear nuclei in the cat, J.Comp. Neurol.1969,136:453-484.
10. E.S.C. Kane, Octopus cells in the cochlear nucleus of the cat:heterotypic synapses upon homeotypic neurons, Int. J. Neurosci. 1973,5: 251-279.
11. J.C. Adams, Single unit studies on the dorsal and intermediateacoustic striae, J.Comp. Neurol. 1976,170: 97-106.
12. E.M. Rouiller, D.K. Ryugo, Intracellular marking of physiologically characterized cells in the ventral cochlear nucleus of the cat, J. Comp. Neurol.1984,225:167-186.
13. L.A. Ritz, W.E. Brownell, Single unit analysis of the posteroventral cochlear nucleus of the decerebrate cat, Neuroscience 1982,7:1995-2010.
14. Snyder RL, Leake PA.Topography of spiral ganglion projections to cochlear nucleus during postnatal development in cats. J Comp Neurol.1997,28;293-311.
15. Frisina RD, Walton JP. Age-related structural and functional changes in the cochlear nucleus. Hear Res. 2006;216-217:216-23.
16. Kazee AM, Han LY, Spongr VP, Walton JP, et al. Synaptic loss in the central nucleus of the inferior colliculus correlates with sensorineural hearing loss in the C57BL/6 mouse model of presbycusis. Hear Res. 1995;89(1-2): 109-20.
1.Li H,Roblin G,Liu H,Heller S.Generation of hair cells by stepwise differentiation of embryonic stem cells.Proc Natl Acad Sci U S A.2003,11;100(23):13495-13500.
2.Rivolta MN,Li H,Heller S.Generation of inner ear cell types from embryonic stem cells.Methods Mol Biol.2006;330:71-92.
3.Li,H.,Liu,H.,Heller,S.Pluripotent stem cells from the adult mouse inner ear.Nat.Med.9,1293-1299.
4.Malgrange B,Belachew S,Thiry M,et all.Proliferative generation of mammalian auditory hair cells in culture.Mechanisms of Development,2002,112(1-2):79-88.
5.Savary E,Hugnot JP,Chassigneux Y,et al.Distinct population of hair cell progenitors can be isolated from the postnatal mouse cochlea using side population analysis.2007,25(2):332-9.
6.Senn P,Oshima K,Teo D,Robust.Postmortem Survival of Murine Vestibular and Cochlear Stem Cells.J Assoc Res Otolaryngol.2007,8(2):194-204.
7.Yerukhimovich MV,Bai L,Chen DH,et al.Identification and characterization of mouse cochlear stem cells.Dev Neurosci.2007,29(3):251-260.
8.Lou X,Zhang Y,Yuan C.Multipotent stem cells from the young rat inner ear.Neurosci Lett.2007,6;416(1):28-33.
9.Jeon SJ,Oshima K,Heller S,et al.Bone marrow mesenchymal stem cells are progenitors in vitro for inner ear hair cells.Mol Cell Neurosci.2007,34(1):59-68.
10.Doyle KL,Kazda A,Hort Y,et al.Differentiation of adult mouse olfactory precursor cells into hair cells in vitro.Stem Cells.2007,25(3):621-627.
11.Kojima K,Tamura S,Nishida AT,et al.Generation of inner ear hair cell immunophenotypes from neurospheres obtained from fetal rat central nervous system in vitro.Acta Otolaryngol Suppl.2004,(551):26-30.
12.Coleman B,Fallon JB,Pettingill LN,et al.Auditory hair cell explant co-cultures promote the differentiation of stem cells into bipolar neurons.Exp Cell Res.2007,15;313(2):232-243.
13.Kageyama R.Nakanishi S.Helix-loop-helix factors in growth and diferentiation of the vertebrate nervous system.Curr Opin Genet Dev.1997,7:659-665.
14.Jan-Jan Liu,June Ho Shin,Krzysztof L,et al.Stem Cell Therapy for Hearing Loss: Mathl Over expression in VOT-E36 Cells. Otology Neurotology.2006,27:414-421.
15. Hasson T, Heintzelman MB, Santos-Sacchi J,et al. Expression in cochlea and retina of myosin Vila, the gene product defective in Usher syndrome type 1B. Proc Natl Acad Sci USA .1995,10;9815-9819.
16. Ninkina NN, Stevens GE, Wood JN, et al. A novel Brn3-like POU transcription factor expressed in Generation of hair cell types from CNS 29 subsets of rat sensory and spinal cord neurons. Nucleic Acids Res 1993; 21:3175_3182.
17. Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cell derived from adult marrow 1 Nature, 2002,418(6893): 412-491.
18. Naito Y, Nakamura T, Iguchi F, et al. Transplantation of autologous mesenchymal stem cells into the cochlea of the chinchilla. Neuroreport,2004,15(1): 1-4.
19. ParkerMA, Cotanche DA1 The potential use of stem cells for cochlear repairlAudiol Neurootol, 2004, 9 (2): 722-801.
20. Yoshida T, Hakuba N, Morizane I, Fujita K, et al. Hematopoietic stem cells prevent hair cell death after transient cochlear ischemia through paracrine effects. Neuroscience. 2007;145(3):923-30.
21. Ito J, Kojima K, Kawaguchi S. Survival of neural stem cells in the cochlear.Acta Otolaryngol, 2001,121 (2): 1402-1421.
22. Tateya I,Nakagawa T, Iguchi F, et al. Fate of neural stem cells graftedinto injured inner ears of mice Neuroreport, 2003, 14 (13) :16772-16811.
23. Sakamoto T, Nakagawa T, Endo T, Kim TS, Iguchi F, Naito Y, Sasai Y,Ito J.Fates of mouse embryonic stem cells transplanted into the inner ears of adult mice and embryonic chickens. Acta Otolaryngol Suppl. 2004 Mar;(551):48-52.
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