Stem cell transplantation for diabetic nephropathy: possibility, feasibility and application

doi:10.3969/j.issn.2095-4344.2014.10.025

Abstract

Abstract:

BACKGROUND: To control blood glucose, blood pressure, blood lipids and inhibit the rennin-angiotensin system is the main idea focused on the treatment of diabetic nephropathy, but the curative effect is unsatisfactory. Hemodialysis and kidney transplantation are suitable for serious cases, however, which is restricted because of the limited source of kidneys and high cost. Regenerative medicine research based on stem cells brings a new hope for treatment of diabetic nephropathy.
OBJECTIVE: To comprehensively analyze the mechanism underlying different sources of stem cells for treatment of diabetic nephropathy and the clinical implications.
METHODS: Papers addressing stem cells for the treatment of diabetic nephropathy were retrieved by computer in CNKI database and PubMed database from January 2005 to August 2013 with the key words “embryonic stem cells, bone marrow mesenchymal stem cells, induced pluripotent stem cells, diabetic nephropathy" in Chinese and English. Papers published recently or in journals with high impact factor were selected. A total of 60 papers were included for review.
RESULTS AND CONCLUSION: Embryonic stem cells, bone marrow mesenchymal stem cells, induced pluripotent stem cells have the potential to differentiate into renal histiocytes. A large numbers of experimental studies have shown that stem cells transplantation has a positive effect on recovery of injured kidney. Stem cell transplantation can provide a novel therapy for diabetic nephropathy.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

全文链接：

Key words: stem cells, diabetic nephropathies, mesenchymal stem cells, multipotent stem cells

CLC Number:

R318

He Yan-qing, Yang Ping. Stem cell transplantation for diabetic nephropathy: possibility, feasibility and application[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(10): 1635-1640.

Figures/Tables 1

2.1 糖尿病肾病的发病机制 2.1.1 氧化应激与糖尿病肾病氧化应激在糖尿病肾病中的可能机制表现为高葡萄糖浓度增加线粒体电子传递链中产生的超氧阴离子[4]。糖尿病患者持续的高糖状态导致了过量的活性氧化物产生，最终形成O2-，OH-和H2O2，从而调整机体DNA，蛋白质和脂类[5]。随着抗氧化酶的失控，氧化应激反应增加导致内皮损伤[6]。此外，活性氧化物上调转化生长因子β1和纤溶酶原激活物抑制物1的表达，导致系膜扩张[7]，晚期表现为糖基化终末产物的积累和肾小球的纤维化。晚期糖基化终产物可能通过对细胞外基质、血管内皮细胞、血管壁的作用，及其受体途径产生微血管损害，从而在糖尿病慢性并发症的发生发展中发挥重要作用。因此，异常的细胞外基质相互作用导致细胞黏附的变化，刺激上皮细胞间质转型[8]。 2.1.2 慢性炎症与糖尿病肾病慢性炎症在糖尿病肾病中起很重要的作用，最近的研究显示，炎症是糖尿病肾病微血管并发症发展的重要因素[9]。同时淋巴细胞、单核细胞和巨噬细胞也参与了糖尿病肾病的进展[10]。白细胞介素1β，白细胞介素6和肿瘤坏死因子α与糖尿病肾病发生发展密切相关[11]。白细胞介素1β增加血管内皮细胞通透性，白细胞介素6发生改变，促进间质浸润，肾小球基底膜增厚，系膜扩张，肾小管萎缩[12]。在糖尿病肾病早期阶段观察到肿瘤坏死因子α的细胞毒性，导致钠潴留和肾脏肥大等[13-14]。因此，上调单核细胞趋化蛋白1和细胞间黏附分子1调控与巨噬细胞和淋巴细胞浸润有关[15]。此外，肿瘤坏死因子α直接促进活性氧簇的局部产生，导致肾小球毛细血管屏障功能障碍，使白蛋白的渗透增加[16]。 2.1.3 肾素-血管紧张素系统与糖尿病肾病有研究显示血管紧张素Ⅱ在糖尿病肾病中分泌增加，导致肾小球系膜和肾小管上皮细胞肥大[17]。同时，其具有导致小动脉平滑肌压力升高的作用，增加血管压力。血管紧张素Ⅱ诱导炎症发生、促进细胞凋亡及产生转化生长因子β和单核细胞趋化蛋白1，这些因子促进肾小球硬化脂肪变性和动脉粥样硬化[18]。这些物质在肾脏脂质沉积产生直接的肾小球损伤，也可导致肾小球系膜细胞的活化和增殖[19]。这些细胞的活化导致趋化因子的产生，从而促进在肾小球系膜区单核细胞和巨噬细胞成熟。此外，低密度脂蛋白不仅可刺激肾小球系膜细胞的增殖，并且增加转化生长因子β和血浆纤溶酶原激活物抑制剂1的表达，其大量集聚在细胞外基质[20]。糖尿病肾病的治疗一直是临床较为棘手的医学难题，治疗思路主要集中在控制血糖、血压、血脂等危险因素以及抑制肾素-血管紧张素系统，但治疗效果并不理想。姑息性治疗策略包括药物来控制血糖，血压和尿蛋白[21]。病情严重者可接受血液透析和肾移植[22]。但肾源有限，费用昂贵，限制肾移植。随着肾功能进一步衰竭，药理干预效果欠佳，例如肾素-血管紧张素系统抑制剂抑制尿白蛋白排泄率在一个相对狭窄的范围内，无法阻止终末期慢性肾脏病进展以及肾功能下降[23]。 2.2 肾干细胞的来源与分布肾干细胞的来源包括胚胎干细胞、肾外来源的成体干细胞及肾内来源的成体干细胞。胚胎干细胞由于涉及到医学伦理学问题其相关研究受到限制，肾外来源的成体干细胞可来自骨髓、脐血或外周血等，来自骨髓的干细胞是目前研究最多的。骨髓内有许多不同类型的干细胞，以造血干细胞和间充质干细胞为主。间充质干细胞是指来源于发育早期中胚层的多能干细胞，不仅存在骨髓中，还存在于脂肪组织、脐血、肝等。还有一类是内皮祖细胞，来源于造血干细胞，也可从外周血中分离，同时也存在于其他组织(骨骼肌、脂肪、脾等)。内皮祖细胞的特性为循环于脉管系统，主要参与血管的形成与修复。此外，近些年来诱导多能干细胞技术的发展揭开了干细胞研究的新篇章，是一类具有广泛应用前景的干细胞。 2.2.1 胚胎干细胞胚胎干细胞是一类具有发育全能性且可在未分化状态下无限增殖的细胞。研究表明，其从胚泡的内细胞团获得多能干细胞；适当的培养条件下即其能分化为内，中，外三胚层细胞[24]。胚胎干细胞虽具有发育的全能性及无限增殖能力，但移植排斥、定向分化的技术障碍、形成畸胎瘤的危险以及伦理等约束是其临床应用前必须要解决的问题。 2.2.2 多能干细胞多能干细胞是指通过导入特定的转录因子将终末分化的体细胞重编程为多能干细胞，多能干细胞技术是干细胞领域革命性的突破，具有广泛的应用前景，多能干细胞具有发育全能性，它可被诱导分化为多种组织细胞，并用于临床治疗[25]。其具有多能性和致畸性，研究者提出多能干细胞应在体外培养和分化。多能干细胞在胚胎组织中发现，因此他们可能从胎儿、新生儿和成年个体分离的。他们都有助于维持细胞稳态和受损的器官再生[26]。由于多能干细胞更少生命伦理学和技术问题，这些细胞已经证明有助于受损肾脏的再生[27]。因此，多能干细胞已被证明分化或转分化为肾系膜细胞[28]，肾小管上皮细胞[29]、内皮细胞[30]、足细胞[31]。 2.2.3 骨髓间充质干细胞骨髓间充质干细胞是存在于骨髓中的非造血细胞。它们在培养中呈贴壁生长，是一类易于扩增，并具有良好可塑性的成体干细胞，其可以分化为成骨细胞、软骨细胞、脂肪细胞、胶质细胞及心肌细胞。研究表明，骨髓间充质干细胞在一定条件下可以分化为肾小球细胞、肾小球系膜细胞和肾小管上皮细胞等肾实质细胞，并发现骨髓间充质干细胞可以选择性地修复外髓质部的部分肾小管坏死，恢复肾小管结构及功能，说明骨髓间充质干细胞具有向肾组织分化的特性和脉管增生的特性。其优点表现为：①来源相对广泛、取材方便。②低免疫原性，并可进行自体移植，显著降低了免疫排斥危险。③易于获得(如从脐血库调集配型相同或相似的脐血)和扩增。④具有良好的可塑性，在损伤信号的诱导下能够分化为各种神经细胞。⑤具有对病变部位的“趋化性”。⑥不仅可通过替代损伤的细胞发挥作用，还可能通过分泌营养因子和调节自体免疫过程来改善损伤部位的微环境，实现保护功能。骨髓间充质干细胞对糖尿病肾病的修复作用：骨髓间充质干细胞促进组织再生，不仅因为其分化潜能，而且具有清除氧化应激作用。其机制可能与有效清除过氧化氢和过氧亚硝基阴离子的能力有关[32-35]。此外，骨髓间充质干细胞具有活性解毒酶的主要机制，防止氧化损伤蛋白质组和基因组[36]。肾小球内皮细胞损伤是各种肾脏疾病的早期损害表现之一，是肾脏疾病进展的关键因素。肾小球内皮细胞修复可能有助于保护肾功能。研究证实通过异基因骨髓移植，在嵌合体小鼠肾小球中发现有少量供者骨髓来源的内皮细胞和系膜细胞[35]。给嵌合体小鼠注射抗Thy1.1抗体诱导成抗Thy1.1肾小球肾炎(系膜增生性肾小球肾炎小鼠模型)，第7天供者骨髓来源的肾小球内皮细胞数目增加超过对照组4倍，供者来源的细胞完全整合到肾小球结构中。系膜细胞作为肾小球基本的细胞成分，对于维持肾小球毛细血管血流和发挥有效肾灌注起重要作用。采用绿色荧光蛋白(GFP)标记的骨髓移植的方法观察了骨髓干细胞向肾小球细胞的分化。在2-24周的观察期内，骨髓移植受体鼠肾小球内的绿色荧光蛋白阳性细胞呈时间依赖性增加，激光共聚焦显微镜显示这些细胞位于肾小球的系膜区，免疫组织化学结果提示它们既不是巨噬细胞也不是T淋巴细胞。该学者将普通小鼠的骨髓移植给IgA肾病模型鼠，发现受体鼠系膜区IgA和C3的沉积、肾小球硬化程度都比未接受骨髓移植的模型鼠轻，血清IgA水平降低，提示植入的骨髓干细胞不仅替代了受体鼠的免疫细胞，而且也可能产生了肾小球细胞。许多学者通过将体外培养的骨髓间充质干细胞移植入糖尿病肾病大鼠体内的方式观察到了骨髓间充质干细胞对糖尿病肾病的改善作用[37]。即通过调节细胞外基质蛋白合成和降解，抑制白细胞浸润和/或纤维化细胞因子的分泌，抑制免疫调节作用[38]。骨髓间充质干细胞能明显抑制由同种异体抗原诱导的T淋巴细胞增殖，可使CD4+和CD8+T淋巴细胞分泌γ-干扰素水平下降，白细胞介素4水平无影响。骨髓间充质干细胞通过抑制T淋巴细胞的增殖和不同功能亚群分泌细胞因子从而抑制免疫反应[39]。此外，骨髓间充质干细胞培养上清抑制单核细胞来源树突状细胞的成熟，使树突细胞分泌白细胞介素12和刺激淋巴细胞增殖能力降低[40]。因此，间充质干细胞间接限制NK细胞和T淋巴细胞的细胞毒性。间充质干细胞促进调节T淋巴细胞，诱导抗原特异性耐受[41]，降低白细胞介素5、白细胞介素12和肿瘤坏死因子α水平，减少白细胞浸润损伤组织[42]。人类CD4+T淋巴细胞根据产生的细胞因子类型不同分Th1和Th2亚群，Th1细胞分泌白细胞介素2、γ-干扰素等，作为攻击性炎症介质，主要参与细胞免疫、介导迟发性变态反应，启动或促进肾组织的炎症和损伤；Th2细胞分泌白细胞介素4、白细胞介素10、白细胞介素13等，作为抗炎性细胞因子，促进体液免疫、抑制细胞免疫，参与肾脏的自身防御，促进炎症消散和组织修复。Th1/Th2细胞因子、攻击因子与防御因子的平衡改变，导致内环境稳定的破坏，决定了肾脏疾病的转归[43]。骨髓间充质干细胞可分泌多种营养因子，包括血管内皮生长因子，碱性成纤维细胞生长因子，血小板衍生生长因子，肝细胞生长因子和表皮生长因子。间充质干细胞在组织再生起重要作用，其趋化至受损组织，通过分泌改善微环境：防止实质细胞死亡；在心肌梗死和急性肾功能衰竭模型[44]，间充质干细胞诱导内源性祖细胞增殖分化，促进血管新生。在急性心肌梗死和急性缺血性肾衰模型虽然外周间充质干细胞是稀缺的(小于外周中的0.01%)[45]，但其能够归巢到受损器官，保护组织内源性组织再生的机制和/或分化为组织特异性细胞。此外，间充质干细胞移植已成功应用在人类患者治疗不同的病症如移植物抗宿主病[46]、脑卒中[47]、心肌梗死[48]、异染性脑白质[49]、特发性再生障碍性贫血[49]、成骨不全症[50]。骨髓间充质干细胞对肾血管肾结构重塑发挥关键作用，可形成间质成纤维细胞，肾小球系膜细胞，足细胞和肾小管上皮细胞[51]；其改善Alport综合征和肾小球肾炎临床症状有重要意义[52]。在急性肾小管上皮细胞损伤实验性肾小球肾炎动物模型中，间充质干细胞有助于恢复肾小球和肾小管的功能和结构[53]；在大鼠残余肾模型中，间充质干细胞移植减轻肾纤维化产生和减少肾小球硬化指数[54]，可能的机制与Ⅰ型胶原表达，Ⅲ型胶原、纤连蛋白、波形蛋白、角蛋白和转化生长因子β减少相关。同时可能改变MMP-9和TIMP-1比值，降解细胞外基质成分，促进细胞内外的平衡[55]。间充质干细胞降低细胞凋亡和增加近端肾小管上皮细胞增殖，肝细胞生长因子诱导间充质干细胞分泌增强，促进重构肾纤维化[56-57]。骨髓间充质干细胞对糖尿病肾功能衰竭的作用：骨髓间充质干细胞可用于预防或逆转糖尿病患者肾功能衰竭。在免疫缺陷的非肥胖糖尿病小鼠模型中，骨髓间充质干细胞大量心内注射后(≈250×106/kg)，在肾脏中发现其供体细胞[58]。无法证实其供体细胞的作用，因为对动物无法行肾功能衰竭的治疗或随访。在低剂量链脲佐菌素诱导的1型糖尿病小鼠模型中，注射间充质干细胞(≈20×106/kg)可降低微量白蛋白尿，减少肾小管坏死[59]。在链脲佐菌素引起2型糖尿病大鼠模型中，心内输注异体间充质干细胞(≈10×106 /kg)与环孢素也可导致肾脏功能和结构的短暂改善[60]。 2.2.4 内皮祖细胞内皮祖细胞来源于造血干细胞，也可从外周血中分离，同时也存在于其他组织(骨骼肌、脂肪、脾等)。内皮祖细胞的特性为循环于脉管系统，主要参与血管的形成与修复。自20年前Nakaham等发现人脐血中含有丰富造血干细胞以来。脐血造血干/祖细胞的研究取得了相当大的进展，并已用于Fanconi’s 贫血、白血病等多种血液系统疾病的治疗。近来研究表明，脐血中的部分细胞在体外培养或体内移植后可分化为肾脏细胞，并可促进糖尿病肾病动物的功能恢复。其主要优势是不需要配型。内皮细胞功能紊乱和微血管损伤被认为是糖尿病肾病的始动因素，研究发现内皮祖细胞可通过使受损内皮细胞再生及血管修复的方式达到治疗糖尿病肾病的目的。用磁性小珠对细胞表面抗原筛选的方法从人外周血中分离出内皮祖细胞，并观察到该细胞可在体外培养分化为内皮细胞。有研究显示内皮祖细胞可以动员至损伤的肾小球处，并参与肾小球毛细血管的再生。"

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