视网膜色素变性大鼠Müller细胞逆分化为视网膜前体细胞的研究
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摘要
视网膜色素变性(Retina pigmentosa)是一种严重的致盲眼病,以光感受器细胞死亡为主要病理特征,临床上缺乏有效的治疗方法。目前很多研究集中在视网膜干细胞移植领域,以期望移植的细胞能够补充并修复视网膜色素变性过程中受损的视网膜光感受器细胞(Tomita et al., 2005) (MacLaren et al., 2006) (West et al., 2008)。虽然视网膜干细胞移植目前仍存在许多问题,如:移植细胞存活数量较少;移植细胞向光感受器细胞分化比例较低;难以验证移植细胞真正参与了宿主视网膜的视觉形成过程等,但是多数实验证实视网膜干细胞移植能够一定程度上改善视网膜色素变性动物模型的视功能(Seiler et al., 2008a) (Wang et al., 2008)Gamm (Gamm et al.)。因此,视网膜干细胞移植仍被认为是治疗视网膜色素变性疾病最具有潜在应用前景治疗方法。
视网膜前体细胞概念的提出让人们从另一个角度认识视网膜损伤后自我修复能力。现在研究已证实,在成年哺乳动物视网膜内多个部位存在视网膜前体细胞(Perron and Harris, 2000)。如:视网膜睫状上皮细胞(Ahmad et al., 2000) (Tropepe et al., 2000)虹膜色素上皮细胞(Haruta et al., 2001) (Asami et al., 2007)等。最近研究发现,成年动物体内的视网膜Müller细胞也具有成为视网膜前体细胞的潜在能力(Fischer and Reh, 2001) (Ooto et al., 2004) (Osakada and Takahashi, 2007)。本实验室既往应用免疫印迹方法研究发现,视网膜前体细胞标记物Chx10表达量在RCS(Roval College Surgery,RCS)大鼠视网膜内呈现出生后减低至消失,而成年又出现增加的趋势。
既往对Müller细胞的认识仅停留在对神经胶质细胞的传统认识上。随着人们对神经胶质细胞认识的深入,发现视网膜Müller细胞具有逆分化为视网膜前体细胞的潜能。在哺乳动物视网膜中Müller细胞在正常情况无法重新进入细胞周期开始逆分化,但是在一些急性损伤的情况下,如:应用NMDA造成小鼠视网膜神经节细胞和无长突细胞死亡(Karl et al., 2008)应用MNU造成大鼠视网膜光感受器细胞死亡(Wan et al., 2008),或是应用激光造成小鼠视网膜急性损伤(Kohno et al., 2006),视网膜Müller细胞均可重新进入细胞周期并逆分化为视网膜前体细胞。同时有研究发现,外源性给予视网膜Müller细胞营养因子,如脑源性神经营养因子(Brain Derived Neurotrophic Factor,BDNF)、胶质源性生长因子(Glia Derived Neurotropic Factor,GDNF)可增强其逆分化能力(Nickerson et al., 2008) (Insua et al., 2008)。然而,这些研究都是停留在急性损伤中,尚未见慢性损伤导致Müller细胞逆分化的报道。综合上述各项研究,结合本实验室既往研究结果,提出假设:RCS大鼠视网膜变性作为一种慢性刺激可导致Müller细胞出现逆分化并开始表达视网膜前体细胞表面标志物。视网膜干细胞移植或联合BDNF移植可增强RCS大鼠视网膜Müller细胞逆分化能力,从而达到延缓视网膜色素变性的作用。
针对以上假设,本文的主要内容及研究结果如下:
1、应用组织化学方法观察RCS大鼠发育过程中视网膜形态变化,发现RCS大鼠视网膜形态改变开始于15天(睁眼时间),30d时达到高峰,90d及120d时属于视网膜色素变性晚期;应用免疫荧光化学技术,研究在RCS大鼠视网膜慢性退行性变过程中,视网膜前体细胞分布特性及变化规律。结果发现,RCS大鼠出生后视网膜前体细胞数量迅速减少,至睁眼(15d)时几乎消失;但在视网膜色素变性高峰期时,视网膜前体细胞又重新出现,并可持续存在至变性晚期;进一步应用视网膜Müller细胞标志物—Vimentin双重标记,发现在RCS大鼠变性高峰期重新出现的视网膜前体细胞来源于视网膜Müller细胞逆分化。结果提示,RCS大鼠视网膜色素变性作为慢性刺激,可以导致视网膜Müller细胞发生逆分化。
2、通过条件培养基及传代培养方法得到的视网膜干细胞具有自我增殖,自我复制和多向分化潜能,能够分化为各类视网膜神经元。经流式细胞仪检测培养3代后的视网膜干细胞纯度较高,可作为本研究中移植的种子细胞。将DiI红色荧光标记的大鼠视网膜干细胞经巩膜外路法移植入30天龄的RCS大鼠视网膜下腔。于60d、90d及120d时检测移植细胞存活、迁徙、分化,以及RCS大鼠视功能改善情况。结果发现,移植细胞在RCS大鼠视网膜内可以存活至120d,并有向视网膜内层迁徙的趋势;初期移植细胞存活数量较多,主要分布在视网膜外核层,后期移植细胞存活数量减少,较多分布在视网膜内核层。视网膜干细胞联合BDNF移植,有利于移植细胞在RCS大鼠视网膜内存活。应用免疫荧光化学技术,检测移植细胞向各种视网膜神经元分化情况,结果发现视网膜干细胞移植或联合BDNF移植后,移植细胞在RCS大鼠视网膜内具有向多种视网膜细胞分化的能力;早期倾向于向光感受器细胞方向分化,晚期则有较多向神经胶质细胞方向分化;联合应用BDNF未见明显促进移植细胞向光感受器细胞分化。应用视网膜电图(ERG)检测RCS大鼠视功能改善情况,Rod-ERG b波及Max-ERGb波振幅及潜时进行统计比较发现,视网膜干细胞移植在术后1月及2月时可改善RCS大鼠视功能,具体表现为Rod-b波及Max-b波潜时的缩短及振幅的增高。联合应用BDNF后,可在术后1月时增强视网膜干细胞移植对RCS大鼠视功能的改善作用。
3、在视网膜干细胞移植术后,应用免疫荧光双标技术,观察RCS大鼠视网膜Müller细胞逆分化情况及视网膜前体细胞分布特点。结果发现,视网膜干细胞移植引起RCS大鼠视网膜前体细胞数量增多,且这些增多的视网膜前体细胞多数来源于视网膜Müller细胞逆分化,即视网膜干细胞移植增强了RCS大鼠视网膜Müller细胞逆分化,且部分逆分化的Müller细胞出现去分化现象,表达视网膜光感受器细胞标志物-Recoverin;然而,PBS伪手术及单纯注射BDNF不能增强RCS大鼠视网膜Müller细胞逆分化。经过定量计数分析比较发现,BDNF联合视网膜干细胞移植有更强的促进Müller细胞逆分化作用。
综上所述,本课题得出如下结论:
1、慢性视网膜色素变性这种刺激因素可以引起RCS大鼠视网膜Müller细胞发生逆分化,表达视网膜前体细胞标志物。2、视网膜干细胞移植或联合BDNF移植后,移植细胞在RCS大鼠视网膜内具有向多种视网膜细胞分化的能力,并显著改善RCS大鼠视网膜功能。3、视网膜干细胞或联合BDNF移植后通过激活视网膜Müller细胞逆分化为视网膜前体细胞和部分去分化为光感受器细胞达到改善RCS大鼠视网膜功能、延缓视网膜变性的作用。
Retina degeneration disease is the leading cause of blindness worldwide, which lack the suitable clinical treatment. Among several experimental approaches for the treatment of retina degeneration, stem cell-based therapy offers a novel therapeutic approach, based on the stratagem that transplanted progenitor cells could replace the lost photoreceptor cells during the degenerative process. In recent years several reports have been published in this field, proved that transplanted retina progenitor cells could integrate into host retina and differentiate into photoreceptors and play an effective way in rescuing vision in animal models of retinal degeneration. However cell-based therapeutic approaches have been limited to date due to the minimal survival and integration of donor cells into the ONL and their ability to participate into host retinal circuitry.
With the scientific development, we know more and more about ourselves. It has long been believed that the adult mammalian central nervous system (CNS) lacked for neurogenesis, but in the last decade it has been proved that continuous neurogenesis occurs at two principal sites: the subventricular zone (SVZ) of the lateral ventricles and the hippocampus. Moreover, radial glia which arises from neuroepithelial cells around the time that neurons begin to appear has long been recognized as scaffolds for immature neurons migrating to the cortical plate during neurogenesis, while recent evidence suggests that the radial glia could participate in neural regeneration and showed multipotential character of neural stem cells in adult mammalian CNS. With regard to the retina, which is a part of the CNS, it has been indicated that Müller cells are the radial glia of the neural retina. Recent studies showed that they could behave as endogenous retina progenitor cells and show the proliferation and regenerating potentials in vitro or in vivo, under certain special conditions. These give people a new sight on treating retinal degeneration disease by using this group of cells. However, most of these in vivo studies performed on the mammalian model of acute retina injure, such as N-methy1-D-aspartate (NMDA) neurotoxin injury, laser injury and N-methy1-N-nitrosourea (MNU). These acute retina degenerations are rare in clinic. Till now no researches focus on the neurons progenitor potential of Müller cells in chronically retinal degeneration pathological process. Our lab found out that Chx10, which is a retina progenitor marker re-expressed during the peak time of retina degeneration of RCS rat and then drop down gradually. Based on all the researches above and the previous results in our lab, we make a hypothesis that Müller could be stimulated into cell cycle during the retina degeneration progress and retina stem cells transplantation.
Based on the hypothesis above, our study initially focused on: 1) investigate whether Müller cells could show potential of regeneration during the pathological process of RCS rats; 2) transplant DiI labeled rat retina stem cells into subretinal space of RCS rat at day 30. Investigate grafts survival, migration, differentiation and rescue effects; 3) investigate whether Müller cells could be stimulated reenter cell cycle and dedifferentiate after retina stem cells transplantation. Our main results are showed as following:
1. Müller cells could show potential of retina progenitor cells during the pathological process of RCS rats. 2. After transplantation, grafts cells could survival, migration and differentiation into photoreceptors. And the most important is that retina stem cells transplantation could rescue the vision function of RCS rat. 3. The proliferating Müller cells dedifferentiate and a sub set of these cells differentiated into photoreceptors after retina stem cells transplantation.
In this study, we found evidence that Müller cells show part of their character of being a retinal progenitor cells during the chronically retina degeneration process in RCS rats. In addition, we found that Müller cells can be activated and differentiate into photoreceptors after retinal stem cells transplantation. Our research also point out a new way of understanding cell-based therapy, which not only replace the photoreceptor by exogenous donor cells but also stimulate endogenous progenitor cells into photoreceptor.
视网膜前体细胞概念的提出让人们从另一个角度认识视网膜损伤后自我修复能力。现在研究已证实,在成年哺乳动物视网膜内多个部位存在视网膜前体细胞(Perron and Harris, 2000)。如:视网膜睫状上皮细胞(Ahmad et al., 2000) (Tropepe et al., 2000)虹膜色素上皮细胞(Haruta et al., 2001) (Asami et al., 2007)等。最近研究发现,成年动物体内的视网膜Müller细胞也具有成为视网膜前体细胞的潜在能力(Fischer and Reh, 2001) (Ooto et al., 2004) (Osakada and Takahashi, 2007)。本实验室既往应用免疫印迹方法研究发现,视网膜前体细胞标记物Chx10表达量在RCS(Roval College Surgery,RCS)大鼠视网膜内呈现出生后减低至消失,而成年又出现增加的趋势。
既往对Müller细胞的认识仅停留在对神经胶质细胞的传统认识上。随着人们对神经胶质细胞认识的深入,发现视网膜Müller细胞具有逆分化为视网膜前体细胞的潜能。在哺乳动物视网膜中Müller细胞在正常情况无法重新进入细胞周期开始逆分化,但是在一些急性损伤的情况下,如:应用NMDA造成小鼠视网膜神经节细胞和无长突细胞死亡(Karl et al., 2008)应用MNU造成大鼠视网膜光感受器细胞死亡(Wan et al., 2008),或是应用激光造成小鼠视网膜急性损伤(Kohno et al., 2006),视网膜Müller细胞均可重新进入细胞周期并逆分化为视网膜前体细胞。同时有研究发现,外源性给予视网膜Müller细胞营养因子,如脑源性神经营养因子(Brain Derived Neurotrophic Factor,BDNF)、胶质源性生长因子(Glia Derived Neurotropic Factor,GDNF)可增强其逆分化能力(Nickerson et al., 2008) (Insua et al., 2008)。然而,这些研究都是停留在急性损伤中,尚未见慢性损伤导致Müller细胞逆分化的报道。综合上述各项研究,结合本实验室既往研究结果,提出假设:RCS大鼠视网膜变性作为一种慢性刺激可导致Müller细胞出现逆分化并开始表达视网膜前体细胞表面标志物。视网膜干细胞移植或联合BDNF移植可增强RCS大鼠视网膜Müller细胞逆分化能力,从而达到延缓视网膜色素变性的作用。
针对以上假设,本文的主要内容及研究结果如下:
1、应用组织化学方法观察RCS大鼠发育过程中视网膜形态变化,发现RCS大鼠视网膜形态改变开始于15天(睁眼时间),30d时达到高峰,90d及120d时属于视网膜色素变性晚期;应用免疫荧光化学技术,研究在RCS大鼠视网膜慢性退行性变过程中,视网膜前体细胞分布特性及变化规律。结果发现,RCS大鼠出生后视网膜前体细胞数量迅速减少,至睁眼(15d)时几乎消失;但在视网膜色素变性高峰期时,视网膜前体细胞又重新出现,并可持续存在至变性晚期;进一步应用视网膜Müller细胞标志物—Vimentin双重标记,发现在RCS大鼠变性高峰期重新出现的视网膜前体细胞来源于视网膜Müller细胞逆分化。结果提示,RCS大鼠视网膜色素变性作为慢性刺激,可以导致视网膜Müller细胞发生逆分化。
2、通过条件培养基及传代培养方法得到的视网膜干细胞具有自我增殖,自我复制和多向分化潜能,能够分化为各类视网膜神经元。经流式细胞仪检测培养3代后的视网膜干细胞纯度较高,可作为本研究中移植的种子细胞。将DiI红色荧光标记的大鼠视网膜干细胞经巩膜外路法移植入30天龄的RCS大鼠视网膜下腔。于60d、90d及120d时检测移植细胞存活、迁徙、分化,以及RCS大鼠视功能改善情况。结果发现,移植细胞在RCS大鼠视网膜内可以存活至120d,并有向视网膜内层迁徙的趋势;初期移植细胞存活数量较多,主要分布在视网膜外核层,后期移植细胞存活数量减少,较多分布在视网膜内核层。视网膜干细胞联合BDNF移植,有利于移植细胞在RCS大鼠视网膜内存活。应用免疫荧光化学技术,检测移植细胞向各种视网膜神经元分化情况,结果发现视网膜干细胞移植或联合BDNF移植后,移植细胞在RCS大鼠视网膜内具有向多种视网膜细胞分化的能力;早期倾向于向光感受器细胞方向分化,晚期则有较多向神经胶质细胞方向分化;联合应用BDNF未见明显促进移植细胞向光感受器细胞分化。应用视网膜电图(ERG)检测RCS大鼠视功能改善情况,Rod-ERG b波及Max-ERGb波振幅及潜时进行统计比较发现,视网膜干细胞移植在术后1月及2月时可改善RCS大鼠视功能,具体表现为Rod-b波及Max-b波潜时的缩短及振幅的增高。联合应用BDNF后,可在术后1月时增强视网膜干细胞移植对RCS大鼠视功能的改善作用。
3、在视网膜干细胞移植术后,应用免疫荧光双标技术,观察RCS大鼠视网膜Müller细胞逆分化情况及视网膜前体细胞分布特点。结果发现,视网膜干细胞移植引起RCS大鼠视网膜前体细胞数量增多,且这些增多的视网膜前体细胞多数来源于视网膜Müller细胞逆分化,即视网膜干细胞移植增强了RCS大鼠视网膜Müller细胞逆分化,且部分逆分化的Müller细胞出现去分化现象,表达视网膜光感受器细胞标志物-Recoverin;然而,PBS伪手术及单纯注射BDNF不能增强RCS大鼠视网膜Müller细胞逆分化。经过定量计数分析比较发现,BDNF联合视网膜干细胞移植有更强的促进Müller细胞逆分化作用。
综上所述,本课题得出如下结论:
1、慢性视网膜色素变性这种刺激因素可以引起RCS大鼠视网膜Müller细胞发生逆分化,表达视网膜前体细胞标志物。2、视网膜干细胞移植或联合BDNF移植后,移植细胞在RCS大鼠视网膜内具有向多种视网膜细胞分化的能力,并显著改善RCS大鼠视网膜功能。3、视网膜干细胞或联合BDNF移植后通过激活视网膜Müller细胞逆分化为视网膜前体细胞和部分去分化为光感受器细胞达到改善RCS大鼠视网膜功能、延缓视网膜变性的作用。
Retina degeneration disease is the leading cause of blindness worldwide, which lack the suitable clinical treatment. Among several experimental approaches for the treatment of retina degeneration, stem cell-based therapy offers a novel therapeutic approach, based on the stratagem that transplanted progenitor cells could replace the lost photoreceptor cells during the degenerative process. In recent years several reports have been published in this field, proved that transplanted retina progenitor cells could integrate into host retina and differentiate into photoreceptors and play an effective way in rescuing vision in animal models of retinal degeneration. However cell-based therapeutic approaches have been limited to date due to the minimal survival and integration of donor cells into the ONL and their ability to participate into host retinal circuitry.
With the scientific development, we know more and more about ourselves. It has long been believed that the adult mammalian central nervous system (CNS) lacked for neurogenesis, but in the last decade it has been proved that continuous neurogenesis occurs at two principal sites: the subventricular zone (SVZ) of the lateral ventricles and the hippocampus. Moreover, radial glia which arises from neuroepithelial cells around the time that neurons begin to appear has long been recognized as scaffolds for immature neurons migrating to the cortical plate during neurogenesis, while recent evidence suggests that the radial glia could participate in neural regeneration and showed multipotential character of neural stem cells in adult mammalian CNS. With regard to the retina, which is a part of the CNS, it has been indicated that Müller cells are the radial glia of the neural retina. Recent studies showed that they could behave as endogenous retina progenitor cells and show the proliferation and regenerating potentials in vitro or in vivo, under certain special conditions. These give people a new sight on treating retinal degeneration disease by using this group of cells. However, most of these in vivo studies performed on the mammalian model of acute retina injure, such as N-methy1-D-aspartate (NMDA) neurotoxin injury, laser injury and N-methy1-N-nitrosourea (MNU). These acute retina degenerations are rare in clinic. Till now no researches focus on the neurons progenitor potential of Müller cells in chronically retinal degeneration pathological process. Our lab found out that Chx10, which is a retina progenitor marker re-expressed during the peak time of retina degeneration of RCS rat and then drop down gradually. Based on all the researches above and the previous results in our lab, we make a hypothesis that Müller could be stimulated into cell cycle during the retina degeneration progress and retina stem cells transplantation.
Based on the hypothesis above, our study initially focused on: 1) investigate whether Müller cells could show potential of regeneration during the pathological process of RCS rats; 2) transplant DiI labeled rat retina stem cells into subretinal space of RCS rat at day 30. Investigate grafts survival, migration, differentiation and rescue effects; 3) investigate whether Müller cells could be stimulated reenter cell cycle and dedifferentiate after retina stem cells transplantation. Our main results are showed as following:
1. Müller cells could show potential of retina progenitor cells during the pathological process of RCS rats. 2. After transplantation, grafts cells could survival, migration and differentiation into photoreceptors. And the most important is that retina stem cells transplantation could rescue the vision function of RCS rat. 3. The proliferating Müller cells dedifferentiate and a sub set of these cells differentiated into photoreceptors after retina stem cells transplantation.
In this study, we found evidence that Müller cells show part of their character of being a retinal progenitor cells during the chronically retina degeneration process in RCS rats. In addition, we found that Müller cells can be activated and differentiate into photoreceptors after retinal stem cells transplantation. Our research also point out a new way of understanding cell-based therapy, which not only replace the photoreceptor by exogenous donor cells but also stimulate endogenous progenitor cells into photoreceptor.
引文
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13. Farrar, G. J., P. F. Kenna, and P. Humphries, 2002, On the genetics of retinitis pigmentosa and on mutation-independent approaches to therapeutic intervention: EMBO J, v. 21, p. 857-64.
14. Fausett, B. V., and D. Goldman, 2006, A role for alpha1 tubulin-expressing Muller glia in regeneration of the injured zebrafish retina: J Neurosci, v. 26, p. 6303-13.
15. Fausett, B. V., J. D. Gumerson, and D. Goldman, 2008, The proneural basic helix-loop-helix gene ascl1a is required for retina regeneration: J Neurosci, v. 28, p. 1109-17.
16. Fimbel, S. M., J. E. Montgomery, C. T. Burket, and D. R. Hyde, 2007, Regeneration of inner retinal neurons after intravitreal injection of ouabain in zebrafish: J Neurosci, v. 27, p. 1712-24.
17. Fischer, A. J., 2005, Neural regeneration in the chick retina: Prog Retin Eye Res, v. 24, p. 161-82.
18. Fischer, A. J., A. Hendrickson, and T. A. Reh, 2001, Immunocytochemical characterization of cysts in the peripheral retina and pars plana of the adult primate: Invest Ophthalmol Vis Sci, v. 42, p. 3256-63.
19. Fischer, A. J., and T. A. Reh, 2001, Muller glia are a potential source of neural regeneration in the postnatal chicken retina: Nat Neurosci, v. 4, p. 247-52.
20. Florian, C., T. Langmann, B. H. Weber, and C. Morsczeck, 2008, Murine Muller cells are progenitor cells for neuronal cells and fibrous tissue cells: Biochem Biophys Res Commun, v. 374, p. 187-91.
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