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ARVO2019丨从科幻到现实
—视神经再生不再是梦

神经眼科学  作者:国际眼科时讯  2019/5/10 11:59:00
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内容概要:在2019ARVO中,干细胞移植方面的进展是一大亮点。

International Ophthalmology: Congratulations on receiving the Dr David L. Epstein Award at ARVO 2019. Can you tell us how you feel about the award?

Dr Johnson: First, I think it is important to note that the award is primarily in Harry Quigley’s honor. The intent of the award is to honor a senior glaucoma specialist who has mentored clinician scientists over the years in a successful way. He has been doing that in outstanding fashion for decades. So many of his prior Fellows are now established Professors or Heads of Departments and have made major contributions to the field. I am very lucky to be one of many who have benefitted from Dr. Quigley’s mentorship. But the award is really special for us, because it gives us a great opportunity. It provides a good deal of research funding that will be useful for me in working with Dr. Quigley on our project over the next two years. It is really an honor to get the award, but also hugely practical for us to continue to do some really important work.

International Ophthalmology: Retinal ganglion cell (RGC) degeneration is a common cause of glaucoma and optic neuropathy, and the main reason for blindness and visual impairment. Can you tell us about the latest cutting-edge research in glaucoma and optic neuropathy?

Dr Johnson: Our work is in trying to develop treatments for glaucoma and other optic neuropathies. I think we are several years away from applying our current work to human patients, but clinical trials in human patients are ultimately the goal. The work we are pursuing is stem cell-derived retinal ganglion cell transplantation. And there are many groups doing great work in this field. I would say that most of the work so far in the realm of optic nerve regeneration has been in trying to figure out how to get retinal ganglion cell axons to grow through the optic nerve and towards the brain. That is a huge challenge that needs to be overcome. But there has been relatively less work on understanding how to make retinal ganglion cells develop new connections within the retina. If we are going to replace ganglion cells in a patient where they have been lost, such as in someone with advanced glaucoma, the connections for each individual ganglion cell need to run in both directions – through the optic nerve and into the brain, and also into the retina. So my work, and what we are going to be studying with the Epstein Award, is aimed at transplanting retinal ganglion cells into the eye, and then devising methods to encourage migration of the transplanted cells into the retina, and once there, to sprout dendrites and begin to make synaptic connections with other retinal cells - the bipolar cells and amacrine cells – so they can absorb the messages from the retina and begin to transmit them through the optic nerve. Right now, we are working in pre-clinical models – tissue culture and rodents. We are working on identifying the obstacles that exist in the mature and diseased retina to the integration of transplanted neurons. We know that if we just inject cells or transplant cells into the eye, there is very poor survival of cells, probably resulting from the relatively harsh inflammatory neurodegenerative microenvironment.  And for those cells that do survive, they tend to just sit on the surface of the retina without integrating with the retinal tissue. The work that we presented at ARVO this year suggested that the internal limiting membrane (ILM), which sits on the surface of the retina and is the basement membrane separating the neuroretinal tissue from the vitreous cavity, serves as a barrier to the cells integrating into the retina. We have developed techniques to digest the ILM, and then when we transplant cells in that context, they are able to send neurites into the retinal tissue where there is then the opportunity to make synapses. Right now, we have done this in an ex-vivo rodent retinal explant system, and we are working on translating that into in-vivo models.

International Ophthalmology: Could you elaborate on the RGC replacement optic nerve regeneration therapy?

Dr Johnson: We are at the stage where we are able to get the neurite processes of the transplanted retinal ganglion cells into the retina. The next stages are going to be understanding what signals control the dendrite patterning of these cells and directing them into the correct sublamina of the inner plexiform layer (IPL). The space where retinal ganglion cells make synapses with bipolar cells and amacrine cells is highly organized into sublamina, and the positions of the dendrites within those layers are related to the properties of the ganglion cells. We know there are probably 30-40 subclasses of retinal ganglion cells, each with unique electrophysiological properties. A lot of that is dictated by which other cells within the retina the retinal ganglion cells are connected to. The next challenge is going to be taking these transplanted ganglion cells, and figuring out how the patterning of their dendrites and their synaptic connections can be controlled in such a way that we are replacing cells with electrophysiological properties that contribute appropriately to vision. At the same time, once the cells are able to make afferent synaptic connections in the retina, they also need to grow a very long axon through the optic nerve and into the brain. We know that the adult optic nerve has several inhibitory signals within it that make it difficult for ganglion cell axons to regenerate, and those will need to be overcome. There are also intrinsic cell properties we can manipulate to increase how well the ganglion cells want to grow. Beyond that, we still need to determine how to guide the axons from the optic nerve through the various visual tracts and streams of white matter in the brain into the vision processing centers. These axons need to end up in the parts of the brain that are responsible for vision and not, for instance, for smell or taste or memory. We are just now beginning to understand what some of those signals are and how to control them experimentally.

International Ophthalmology: Could you talk about the neuroprotective effects of stem cells on RGC degeneration?

Dr Johnson: There are several different types of stem cells that have neuroprotective properties. The ones I did the most work on myself were bone marrow-derived mesenchymal stem cells. These are nice because you can take them from an adult patient via a bone marrow biopsy. You can transplant them back into the same patient you are treating, so they are readily available and you don’t need to worry about immunologic rejection. For a time, we were interested in whether we could take those cells and transdifferentiate them into retinal ganglion cells. I don’t know that many people have been successful doing that in a convincing manner, but we did find that they have other properties that could be therapeutically useful. They secrete neurotrophic factors, growth factors and anti-inflammatory factors that are highly protective for retinal ganglion cells. We identified several key growth factors several years ago, one of which was platelet-derived growth factor (PDGF), but they also secrete brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CTNF). More recent work has very nicely shown the manner in which these proteins are secreted. They are not just dumped into the extracellular space, but rather secreted in extracellular vesicles, called exosomes. They then can be taken up by the retinal ganglion cells in a rather specific manner. Whether stem cell transplantation for neuroprotection using mesenchymal stem cells is going to be a therapy for use in humans is not clear, but at least better understanding the scientific basis of why mesenchymal stem cells are protective gives us targets to develop drugs that work through the same pathways.

International Ophthalmology: How soon do you expect RGC replacement optic nerve regeneration therapy to be used as standard treatment?

Dr Johnson: It is difficult to even speculate on a timeframe. The problem at this point is that there are probably things we don’t even recognize we don’t know yet. We need to get to the stage of having retinal ganglion cells that have directed dendrites into the retina to be able to discern what the obstacles are to patterning those dendrites correctly in the inner plexiform layer and to forming functional synapses. We need to get axons to grow through the optic nerve to vision-related brain nuclei before we can understand what problems might arise when it comes to patterning a retinotopic map or generating synapses there. So, it is difficult to know. I think it is going to be several years at this point.

International Ophthalmology: At this ARVO Meeting, what have you found to be of interest in your field?

Dr Johnson: There are a couple of other people doing really great work on stem cell transplantation. This is an exciting time. I have been coming to ARVO since 2006. When I first started coming, people were presenting work on RGC neuroprotection and it new, cutting edge stuff – a therapy of the future. Now, we are getting very close to having clinically available neuroprotective therapies. I think that is on the near horizon. The idea of stem cell transplantation for optic nerve regeneration ten years ago was total science fiction.  Some people thought it would never be done. Just a few years ago, the US National Eye Institute labeled it an audacious goal and set up a mechanism to fund projects to achieve that. Now, at this ARVO, there are several groups looking at stem cell transplantation for optic nerve regeneration. A couple of investigators in particular are doing great things. Petr Baranov at Harvard is presenting some really nice work on ways to increase the survival of stem cells after they have been transplanted into the eye. Through this meeting, we are actually beginning a collaboration together to work on that further. I think there has been a lot of exciting progress. Optic nerve regeneration is such a monumental task that it is only going to be done with people in labs all over the world working together and collaborating. Given enough effort and enough resources, we will get there.

在2019ARVO中,干细胞移植方面的进展是一大亮点。遥想2006ARVO,人们像谈论科幻小说一样谈论神经保护研究。十几年后的今天,临床可用的神经保护疗法已经近在咫尺。十年前,干细胞移植用于视神经再生的想法也同样是异想天开,而在2019ARVO上,一些团队报道了用于视神经再生的干细胞移植研究,这是非常伟大的创举。通过这次会议,各国的研究者实际上正在开展合作,共同努力。会议期间,来自约翰·霍普金斯大学的Thomas V.Johnson教授荣膺Epstein奖项,以鼓励他在干细胞移植用于视网膜神经节细胞置换(RGC)和视神经再生领域的杰出成就。会后,《国际眼科时讯》有幸采访了Johnson教授,对干细胞衍生的视网膜神经节细胞移植研究做出了深入阐述。

视神经重新连接大脑?——体外实验成果颇丰
 
目前为止,视神经再生领域的大部分工作都在试图找出如何使视网膜神经节细胞轴突通过视神经生长到大脑。这是一个需要克服的巨大挑战。但是,在了解如何使视网膜神经节细胞在视网膜内形成新的连接方面的工作相对较少。作为一个“双向通道”, 每个神经节细胞需要向两个方向进行连接- 视神经和视网膜。因此,一旦将视网膜神经节细胞移植到眼睛中,就会面临两个问题:如何让它迁移到视网膜?如何让它与其他视网膜细胞 - 双极细胞和无长突细胞形成突触连接?这两点是移植细胞在视网膜上发挥作用的基础,因为如果只注射细胞或将细胞移植到眼睛中,细胞的存活率将会非常低,而侥幸存活的细胞往往只是附着在视网膜表面,没有与视网膜组织整合。Johnson教授透露,目前团队的进展还在临床前模型阶段,包括组织培养和啮齿动物模型,已经在离体啮齿动物视网膜外植体系统中完成了这项工作,但人类患者的临床试验将是最终目标。他还介绍了在2019ARVO上团队展示的工作:有证据表明内界膜(ILM)作为将视神经视网膜组织与玻璃体腔分开的基底膜,可作为屏障阻挡细胞进入视网膜,而团队开发的ILM消化技术,可使移植细胞能够将神经突送入神经组织,进而有机会形成突触连接。
 
路漫漫其修远——视神经再生疗法研究的挑战
 
在成功使移植细胞将神经突送入神经组织后,接下来的目标就是控制这些细胞的树突并使它们正确进入内丛状层(IPL)的正确子层。视网膜神经节细胞与双极细胞和无长突细胞形成突触的空间,此空间组织成严密的亚层,其中树突的位置与神经节细胞的特性相协调,已知可能有30-40个视网膜神经节细胞亚类,每个细胞的性质略有不同。其中很多是由它们所连接的视网膜中的其他细胞决定的。了解单个神经节细胞的树突和突触连接的模式,进而找到相似的方式对细胞的性质进行调控,最终才能用具有实际意义的电生理特性的替换细胞替代视神经内的细胞。
 
细胞在视网膜中产生传入的突触连接的同时,还需要生长长轴突通过视神经并进入大脑。Johnson教授表示,已经发现了成人视神经内部有抑制神经节细胞轴突再生的信号。可以利用细胞的固有特性控制神经节细胞生长的程度。环境中还存在需要调节或抑制的信号,以使视神经细胞更好地生长。除此之外,如何引导视神经轴突经过大脑中的各种区域精确地进入视觉处理中枢尚不明确。
 
Johnson教授还表示,目前还无法预测RGC置换视神经再生疗法的时间范围。目前的进展甚至也许不足以发现这其中的问题。需要先将视网膜神经节细胞整合到视网膜中,才能够发现人工建立突触的障碍;需要让轴突向大脑生长,才能挖掘出视网膜信号转导或突触生成时存在的障碍。这可能需要大量研究人员多年的努力。
 
暗夜曙光现——干细胞对RGC变性的神经保护作用或带来新的机会
 
虽然不同类型的干细胞具有不同的特性,但是神经保护作用的机制是什么?进一步的研究也许能为我们揭示一些答案。通过骨髓活检从成年患者中获得的骨髓来源的间充质干细胞来源广泛,患者接受度好,对此进行的研究发现骨髓来源的间充质干细胞能够分泌神经营养因子、生长因子和抗炎因子,对视网膜神经节细胞具有高度保护作用。几个关键的生长因子包括血小板衍生生长因子(PDGF)、脑源性神经营养因子(BDNF)和睫状神经营养因子(CNTF)等。它们被分泌在细胞外囊泡中,称为外泌体。外泌体漂浮在环境里,并可以以特定的方式被视网膜神经节细胞摄取。干细胞移植对于使用间充质干细胞进行神经保护是否会成为一种用于人类的疗法尚不清楚,但至少更好地理解间充质干细胞为何具有保护作用的科学依据,以此为引,或能开发相应的药物作用于这一途径或者目标受体。
 
在采访的最后,Johnson教授表示,2019 ARVO会议有很多令人兴奋的进展。干细胞移植视神经再生是一项艰巨的任务,只有世界各地的研究人员共同合作才能完成。足够的努力加上足够的资源,锲而不舍,方能将此壁垒一举击破。
 
Thomas V. Johnson教授与Epstein Award
 
Epstein奖是为纪念 David L. Epstein教授而设立,他被公认为是过去四十年以来青光眼研究领域最具影响力的领导者之一。该奖项旨在支持眼科有前景的临床医师或科学家,使得 David L. Epstein教授治愈青光眼的愿景得以传承,让大家铭记他通过科学研究解决青光眼的复杂问题以及寻找疾病病因和新疗法的坚定信念。2019年ARVO会议,来自霍普斯金大学威尔默眼科研究所的Harry A. Quigley教授和Thomas V. Johnson教授荣膺此奖项,以支持他们对干细胞移植用于视网膜神经节细胞置换(RGC)和视神经再生领域的研究。采访中,Johnson教授表示,该奖项主要以Harry A. Quigley教授的荣誉为主。 Quigley教授是一位级别很高的青光眼专家,几十年以来,成功地培养了诸多临床眼科医师,现在他的许多弟子都已成为眼科教授或眼科相关部门负责人,为青光眼领域做出了巨大贡献。Johnson教授也是众弟子之一,他表示,Epstein奖对他们来说意义非凡,为他们提供了大量的研究经费,对未来的研究工作带来了非常大的帮助,得以真正实现David L. Epstein教授的愿景,造福更多青光眼患者。

 


 
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