外泌体在眼底疾病发病及治疗中的作用

外泌体是细胞内的多囊泡体通过与细胞质膜融合后主动分泌到细胞外的小囊泡。外泌体内含有多种活性物质,其在细胞间通讯、疾病进展及作为生物标记物方面的作用已渐被眼底疾病的学者关注。研究显示外泌体参与了湿性年龄相关性黄斑变性病理过程,而间充质干细胞外泌体能够降低湿性年龄相关性黄斑变性患者的血管内皮生长因子转录和翻译;在大鼠糖尿病性视网膜病变血浆中研究发现含有IgG的外泌体可激活视网膜内的经典补体途径促进内皮损伤,应用含有miR-126间充质干细胞衍生的外泌体可限制内皮细胞损伤;在缺血性视网膜病变研究中骨髓间充质干细胞的外泌体可使缺血模型鼠视网膜功能恢复;玻璃体切除联合人脐带组织分离的间充质干细胞外泌体填塞对黄斑裂孔具有辅助治疗作用;视网膜脱离患者使用间充质干细胞分泌的外泌体可抑制光感受器细胞的凋亡;在葡萄膜黑色素瘤患者中外泌体标记物检测有希望成为葡萄膜黑色素瘤的早期诊断手段;在早产儿视网膜病变中小胶质细胞分泌的外泌体具有保护作用等。对外泌体系统的了解及其与眼底疾病中的信号传递机制及疾病转归过程的认识,对优化眼底疾病防治具有重要意义。（国际眼科纵览,2020, 45：442-448）     

干细胞移植治疗青光眼的研究进展

青光眼是以视网膜神经节细胞(retinal ganglion cells,RGC)丢失导致不可逆性视力减退和视野丧失为特征的退行性视神经病变。干细胞具有全能性和自我更新的特性,干细胞治疗已被证明可用于视网膜退行性疾病的治疗,有望成为青光眼视功能恢复的有效手段。干细胞根据来源可分为胚胎干细胞、诱导多能干细胞和成体干细胞,在青光眼治疗中的移植方式包括前房移植、玻璃体内移植、视网膜下和脉络膜上腔移植。干细胞治疗青光眼的途径主要包括修复受损小梁网以降低眼压,以及替代或修复受损伤的RGC。目前干细胞移植治疗青光眼主要存在操作安全性、致瘤性及免疫排斥等问题。通过提取间充质干细胞外泌体和细胞外囊泡的治疗方式可能是较好的解决途径之一。     

间充质干细胞来源的外泌体对糖尿病视网膜病变的作用

外泌体是直径为40-100 nm的细胞外囊泡,其中含有蛋白质、miRNA等多种功能活性物质,并经由不同途径转运至细胞内。研究证实,外泌体能延缓糖尿病视网膜病变的病程进展,通过不同方式,包括直接调控和递送不同的miRNA、长链非编码RNA调控细胞增殖/凋亡因子、抗氧化调控因子、炎症因子、血管内皮生长因子等水平的变化,进而抑制高糖引起的视网膜炎症、新生血管形成、微血管损伤及血管渗漏等视网膜损伤。文章就外泌体的基本特征及其在糖尿病视网膜病变疾病中的研究进展进行系统综述。     

间充质干细胞源性外泌体治疗角膜及眼表疾病的研究进展

间充质干细胞(MSCs)来源的外泌体可通过携带的蛋白或核酸等物质调节局部炎症反应、血管生成及免疫应答,从而为角膜外伤、干眼及免疫性眼病等的治疗提供了新思路。外泌体非细胞的特性避免了干细胞治疗中细胞存活、肿瘤发生及移植物排斥等问题,并且有成为治疗药物的生物载体的潜力。本文拟介绍近年来间充质干细胞源外泌体在角膜及眼表疾病治...     

间充质干细胞联合他汀类药物在糖尿病视网膜病变中的应用研究进展

糖尿病视网膜病变(DR)是糖尿病患者常见的眼部并发症,也是成人盲的主要原因之一.DR现有的治疗方法包括手术和激光治疗等不能从根本上治疗DR.近年研究发现应用间充质干细胞(MSCs)对DR进行细胞治疗具有广泛的应用前景.MSCs具有再生潜能并在视网膜的修复中起作用,但移植后MSCs的生存能力及归巢能力差,降低了其治疗效率.他汀类药物除具有调脂作用外,还能促进MSCs的增生并抑制MSCs凋亡.本文就MSCs联合他汀类药物在DR治疗中的应用及机制进行综述.     

间充质干细胞在视网膜疾病研究中的应用

间充质干细胞(mesenchymal stemcells,MSCs)是一类存在于间质组织具有多向分化潜能的干细胞,被广泛应用于组织或细胞的修复或替代的研究中。利用MSCs分化成为视网膜细胞的研究可为一些视网膜不可逆性病变的治疗带来希望。此外,已有研究表明MSCs分泌的一些细胞因子,有助于提高病理状态下的神经细胞存活能力,利用MSCs的这一功能可为病变视网膜提供保护作用。因此,MSCs的神经保护功能也逐渐被应用于视网膜疾病研究中,成为关注的另一焦点。我们着重介绍了MSCs特征及其在视网膜疾病研究中的一些现状。     

外泌体在糖尿病视网膜病变的机制研究进展

外泌体是广泛存在于人体，由机体细胞产生并分泌的纳米级细胞外囊泡，能相对稳定地存在于各种生物组织和体液中，并携带特定的miRNA、蛋白质、转录因子等多种信息分子，参与调控体内多种疾病的病理生理过程。近年来随着外泌体在各学科研究的不断深入，其在眼科学领域的研究也迅速开展，目前发现外泌体在糖尿病视网膜病变、年龄相关性黄斑变性、自身免疫性葡萄膜炎、角膜病及青光眼等多种疾病中发挥重要作用。随着生活水平的提高，全世界糖尿病视网膜病变致盲人数逐年增加，而糖尿病视网膜病变机制研究未明，近年许多研究发现外泌体在其中发挥着重要作用，本文对外泌体在糖尿病视网膜病变的发生、发展机制的最新研究进展进行综述。     

间充质干细胞在视网膜疾病中的临床应用展望

间充质干细胞(MSC)用于治疗视网膜疾病有两种移植方法:全身静脉注射和局部移植,后者具有更好的针对性。根据疾病不同,需要采用不同的MSC治疗策略:(1)MSC定向分化替代受损细胞,如光感受器细胞和视网膜色素上皮细胞;(2)利用其免疫抑制作用治疗自身免疫性葡萄膜视网膜炎;(3)利用其神经保护作用减轻或延缓视网膜组织损伤,如目前的视网膜色素变性、视网膜缺血再灌注损伤和青光眼动物模型;(4)转基因后的MSC移植靶向治疗,如脉络膜新生血管的治疗;(5)利用MSC抗炎和促进创伤愈合作用治疗多种视网膜疾病。迄今为止,其抑制葡萄膜视网膜炎进展以及视神经营养保护作用较为明确。但MSC在各种视网膜疾病中的疗效还需要严格评估,其发挥作用的机制尚未完全明了,不同研究结果差异较大。此外,MSC的移植途径和方法,治疗的远期效果及安全性也有待进一步评估。     

间充质干细胞源性外泌体对前部缺血性视神经病变患者的治疗潜力

前部缺血性视神经病变(anterior ischemic optic neuropathy,AION)是继青光眼后成人永久性视神经相关视力丧失的第二大常见原因,目前尚无确切有效的治疗方案。既往研究发现间充质干细胞源性外泌体(mesenchymal stem cells-exosomes,MSC-exosomes)与MSCs非常相似地改善缺血后神经组织的损伤,并诱导与增强血管神经发生相关的长期神经保护作用。外泌体是细胞-细胞间交流的一种重要通讯途径,因此可作为小分子物质传递载体信号,并通过不同机制作用于靶细胞,从而成为眼前部缺血性视神经病变潜在的有效治疗工具。本文对MSC-exosomes的生物发生及其功能,以及MSC-exosomes在前部缺血性视神经性病变中的治疗机制进行综述。     

视网膜损伤：外泌体转录组学的研究进展

衰老、缺氧、高糖刺激等多种因素导致的视网膜损伤过程中,外泌体发挥着重要作用。外泌体是一种纳米级的细胞外囊泡,包含微小RNA、环状RNA等多种转录产物,广泛参与视网膜色素上皮细胞损伤、新生血管形成、视网膜神经节细胞和光感受器细胞凋亡等过程。通过转录组学分析外泌体对视网膜损伤及修复的调控机制,识别糖尿病视网膜病变、青光眼等眼科疾病相关分子生物标志物,寻找新的治疗靶点,已成为视网膜研究的热点。因此,本文对外泌体转录组学在视网膜损伤中的研究进展进行综述。     

间充质干细胞外泌体对眼部疾病的治疗作用

间充质干细胞(mesenchymal stem cells,MSCs)是一种来源于多种组织,具有多向细胞分化潜能和自我细胞更新的多能干细胞,可对多种眼部疾病发挥治疗作用。研究表明,MSCs的生物学功能与其分泌的外泌体(MSC-Exo)有密切联系。相较而言,MSC-Exo的生物性能更加稳定,且不具有成瘤性,因此有望成为MSCs生物学功能的有效替代物。本文对MSC-Exo在眼部疾病中的应用进展讨论,以期为MSC-Exo在眼部疾病的治疗提供思路和借鉴。     

Amelioration of diabetic retinopathy by engrafted human adipose-derived mesenchymal stem cells in streptozotocin diabetic rats

Background  

Diabetic retinopathy is a common complication of diabetes, which is caused by injury to retinal microvasculature and neurons. Mesenchymal stem cells (MSCs), which proved to have multi-linkage differentiation capacity, including endothelial cells and neurons, might be a promising cell therapy resource. The current pilot study was performed using the streptozotocin (STZ) rat model of diabetic retinopathy injected intravenously with human adipose-derived mesenchymal stem cells (AMSCs) in an effort to investigate the potency and possible therapeutic effects of AMSCs.     

Aging and retinal vascular diseases

Ocular vascular diseases such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration, whose population increases along with aging, have become leading causes of severe visual disturbance. Macular edema and serous retinal detachment are associated with abnormal vascular leakage and tractional retinal detachment, and neovascular glaucoma is caused by retinal neovascularization. Such ocular vascular diseases are caused by vascular cell aging and vascular damage associated with lifestyle-related diseases including diabetes mellitus, hypertension, hyperlipidemia, and obesity. In the present study, we investigated molecular mechanisms in such vascular deficiencies using vascular cell biology methodology, and we propose novel strategies for the treatment of such vascular diseases. Along with aging, oxidative stress and physical stress, such as mechanical stretch, continuously and directly insult vascular cells. Such stress induces apoptosis by intracellular signaling through stress kinases in cultured retinal vascular cells. Inhibition of such stress kinases could be an effective treatment to protect the vascular cells against age-related damage. In a retinal vascular developmental model, pericyte loss causes pathology mimicking macular edema and proliferative diabetic retinopathy. Angiopoietin 1 (Ang 1) secreted by pericytes suppresses oxidative stress-induced intracellular signaling through stress kinases linked to cell apoptosis and normalizes such retinal pathology. This suggests that the paracrine action of Ang 1 in the pericytes is necessary to sustain normal retinal vasculature, and that Ang 1-triggered intracellular signaling is useful for the treatment of vascular cell pathology associated with pericyte loss. In diabetic retinopathy and retinal vein occlusion, retinal vessels regress along with retinal vascular cell apoptosis, and the retina becomes ischemic followed by pathological retinal neovascularization. VEGF has been recognized as a predominant factor to induce the ischemic retinal neovascularization. We found that retinal vascular cells have a characteristic pattern in VEGF receptor expression, which causes vascular pathology more frequently in the retina than in other organs. Neuropilin 1 (NRP 1), which enhances VEGF receptor function, is abundantly expressed in the retinal endothelial cells and is upregulated by VEGF itself and by hypoxia to regulate a positive feedback mechanism in retinal neovascularization. This receptor could be a unique target for retina-specific therapy. Lifestyle-related diseases increase along with aging and have further increased due to changes in Japanese lifestyle imitating that of Western countries. We found that the renin-angiotensin system which regulates hypertension and cardiovascular diseases, and adipocytokines which are abnormally secreted in obesity, act as proangiogenic factors. Regulation of such lifestyle-related disease factors is important for the treatment of retinal vascular diseases. Finally, we found that erythropoietin is an ischemia-induced angiogenic factor that acts independently and as potently as VEGF in proliferative diabetic retinopathy (PDR). Our study utilizing human vitreous samples demonstrates that the VEGF level is particularly high and strongly associated with angiogenic activity in PDR patients. The potential of VEGF inhibitors has recently been recognized in clinical applications. The manipulation of each angiogenic factor and adipocytokine that we report here could become potential therapy in the near future.     

Mesenchymal stem cells and potential applications in treating ocular disease

Mesenchymal stem cells (MSCs) are remarkable in stem cell biology. Not only do they have significant tissue regeneration potential, but more recently their paracrine effects (either innate or through genetic augmentation) have become increasingly recognized as useful therapeutic approaches. In particular, clinical roles for MSC therapy in neuroprotection and immune suppression are likely to emerge. These therapeutic effects will be particularly advantageous in work on neurological tissues, because MSC-based molecular therapy could overcome some of the difficulties of long-term drug delivery to tissues, such as the eye, which are relatively inaccessible to systemic delivery (for example due to the blood retina barrier). MSC therapy is, therefore, poised for significant impact in ocular molecular therapeutics, particularly for chronic diseases, such as retinal degeneration, glaucoma, and uveitis. Other molecular and tissue regeneration effects of MSCs are also likely to have impact in the management of ocular surface disease and oculoplastics.     

Mesenchymal stem cells for retinal diseases

Retinal diseases are featured with the common result of retinal cell apoptosis that will cause irreversible vision loss. Various attempts have been made for the solution against cell death. However, few approaches turn out to be effective. With the progress in mesenchymal stem cells (MSCs) research, MSCs were considered as a promising source for cell replacement or neuroprotection in retinal disorders. MSCs have the property of self-renewal and are multipotent cells derived from various mesenchymal tissues, which were demonstrated being capable of differentiating into multilineage tissue cells. Some works were also done to differentiate MSCs into retinal cells. MSCs could be induced to express retinal cell markers under certain stimuli. Recent studies also suggest that MSCs should be an ideal source for neuroprotection via the secretion of a variety of neurotrophins. Engineered MSCs were also used as vehicles for continuous delivery of neurotrophins against retinal degeneration with encouraging results. Since there are still barriers on the differentiation of MSCs into functional retinal cells, the use of MSCs for neuroprotection in retinal diseases seems to be a more practicable approach and worthy of further investigations.     

Could donor multipotent mesenchymal stromal cells prevent or delay the onset of diabetic retinopathy?

Diabetes mellitus is a complex metabolic disease that has become a global epidemic with more than 285 million cases worldwide. Major medical advances over the past decades have substantially improved its management, extending patients’ survival. The latter is accompanied by an increased risk of developing chronic macro‐ and microvascular complications. Amongst them, diabetic retinopathy (DR) is the most common and frightening. Furthermore, during the past two decades, it has become the leading cause of visual loss. Irrespective of the type of diabetes, DR follows a well‐known clinical and temporal course characterized by pericytes and neuronal cell loss, formation of acellular‐occluded capillaries, occasional microaneurysms, increased leucostasis and thickening of the vascular basement membrane. These alterations progressively affect the integrity of retinal microvessels, leading to the breakdown of the blood–retinal barrier, widespread haemorrhage and neovascularization. Finally, tractional retinal detachment occurs leading to blindness. Nowadays, there is growing evidence that local inflammation and oxidative stress play pivotal roles in the pathogenesis of DR. Both processes have been associated with pericytes and neuronal degeneration observed early during DR progression. They may also be linked to sustained retinal vasculature damage that results in abnormal neovascularization. Currently, DR therapeutic options depend on highly invasive surgical procedures performed only at advanced stages of the disease, and which have proved to be ineffective to restore visual acuity. Therefore, the availability of less invasive and more effective strategies aimed to prevent or delay the onset of DR is highly desirable. Multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs), are promising healing agents as they contribute to tissue regeneration by pleiotropic mechanisms, with no evidence of significant adverse events. Here, we revise the pathophysiology of DR to identify therapeutic targets for donor MSCs. Also, we discuss whether an MSC‐based therapy could prevent or delay the onset of DR.     

骨髓间充质干细胞治疗视网膜新生血管性疾病的研究进展

视网膜新生血管性疾病并非独立的一种眼病,常见于许多眼病中,如早产儿视网膜病变、糖尿病视网膜病变、年龄相关性黄斑变性、视网膜中央静脉阻塞和视网膜静脉周围炎等都会形成新生血管,是严重损害视力的病变。此类疾病丧失正常血管的结构和功能,引起病理性出血、渗出、水肿和视网膜脱离等病理性改变,是视力丧失的主要原因,已经成为世界范围的致盲性疾病。目前主要的治疗方法为针对病因进行激光封闭,或行玻璃体切除术,或是反复、多次玻璃体腔注射抗血管内皮生长因子,虽然短期效果好,但不能防止复发,目前仍没有长期有效的治疗方法。干细胞治疗的出现为此提供了潜在的替代疗法。本文将对骨髓间充质干细胞(bone marrow mesenchymal stem cells,BMSCs)在视网膜新生血管疾病中的最新应用进展作一综述,展示其移植优势和良好的临床应用前景。