干细胞转化技术是干细胞基础和未来临床移植研究的基石

doi:10.3969/j.issn.2095-4344.2016.01.023

摘要/Abstract

摘要：

文章快速阅读：

文题释义：

血管内皮生长因子：是一种强有力的血管生成因子，新生的血管内皮细胞可形成“血管龛”，通过释放某些神经营养因子促进神经发生。新生的神经细胞也可促进血管发生，二者之间存在“交叉对话”，血管内皮生长因子在其中发挥着非常重要的媒介作用。

共培养：目前已成为流行的干细胞培养方法。共培养分为2种，接触共培养是指将干细胞与某种成体细胞放在一起保持接触，优点是促进两种细胞更多分泌酶或因子及细胞融合，增加干细胞的转化率，而且可以开展三维培养，缺点是难以避免两种细胞间的相互污染。非接触共培养是指将两种细胞放在一起，但用具有渗透性的物质隔开，优点是能避免两种细胞间的相互污染，缺点是限制了细胞间的密切接触，影响了细胞间的信号传导，减弱了干细胞的分化效率。

背景：干细胞转化技术研究已成为干细胞研究的一个活跃领域，对干细胞基础研究及临床研究均产生巨大的推动作用。

目的：对干细胞转化技术研究现状及进展做一综述。

方法：在标题和摘要中，以“Stem cells,Transformation, differentiation”或“干细胞，转化，分化”为主题检索词，检索中国期刊全文数据库(CNKI)、PubMed数据库中2000年1月至2015年4月关于干细胞分化技术的文章。优先选择近期发有或发表在权威杂志上的文章。初检得到121篇文章，根据纳入标准，选择其中的64篇进行综述。

结果与结论：干细胞转化技术近些年来取得了较大的进展，包括改进培养液的配比，增加特定的诱导因子、蛋白质、酶、受体，注射特定的基因，使用新氧化剂，改善培养微环境，在低氧环境下培养，使用支架，采用转基因技术，三维球形培养，共培养等。干细胞转化新技术的诞生和使用，显著提高了干细胞的转化率，为人类难治性疾病的治疗带来希望。

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

ORCID: 0000-0001-5435-8225(涂雪松)

关键词: 干细胞, 移植, 诱导多能干细胞, 间充质干细胞, 骨髓间充质干细胞, 神经干细胞, 胚胎干细胞, 精原干细胞, 肌肉干细胞, 贴壁培养, 共培养, 三维培养, 支架, 增殖, 分化, 转化

Abstract:

BACKGROUND: Stem cell conversion technology has become an active area in the field of stem cell research, and it also has a tremendous boost on both the stem cell basic research and clinical study.
OBJECTIVE: To review the research status and the current progress of stem cell conversion technology.
METHODS: In the titles and summaries, the “stem cells, conversion, differentiation” in Chinese and English served as the search terms to search articles related to stem cells technology published from January 2000 to April 2015 in CNKI and PubMed databases. The latest articles or articles published on the authoritative journals
were preferred. Totally 121 articles were obtained after initial survey, and according to the inclusion criteria, 64 articles were selected for overview.
RESULTS AND CONCLUSION: The progress of stem cells conversion technology has driven the development of the entire stem cell research, including modifying the ratio of culture medium, increasing specific inducers, proteins, enzymes or receptors, injecting specific genes, using new oxidizing agents, modifying culture microenvironment, culture under hypoxia, scaffold usage, applying transgenic technology, three-dimensional spherical culture or co-culture. Stem cell conversion technology will definitely increase the conversion rate of stem cells, which can bring hope for the treatment of refractory diseases.

涂雪松. 干细胞转化技术是干细胞基础和未来临床移植研究的基石[J]. 中国组织工程研究, 2016, 20(1): 128-134.

Tu Xue-song. Stem cell conversion technology is a footstone for stem cell basic and clinical research in the future[J]. Chinese Journal of Tissue Engineering Research, 2016, 20(1): 128-134.

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引言

干细胞转化技术是研究如何安全、有效地将干细胞转化为另一种干细胞或成体细胞的技术。近些年，干细胞转化技术极大地带动了干细胞转化基础研究的进展。人类已能利用干细胞转化技术，将干细胞转化为人体内所有的细胞。美国约翰霍普金斯大学的研究人员利用干细胞转化技术，将诱导多能干细胞转化为视网膜前体细胞，再将视网膜前体细胞培育成视网膜组织功能性感光细胞^[1]。日本理化研究所的 Kadoshima等^[2]开发了一种新型的细胞培养技术，将人类胚胎干细胞诱导成为大脑皮质细胞。在干细胞转化技术的推动下，干细胞移植研究，不论在迁移、分化、作用、作用机制，还是在安全性等方面，近些年均得到长足进展。Ng等^[3]的研究显示，移植的干细胞具有定向迁移到病灶的能力。Xiang等^[4]的研究发现，移植的间充质干细胞具有定向迁移至受损组织器官(“归巢”)的特性。Jensen等^[5]的研究发现，神经干细胞移植后，不但能迁移到受损神经区域，而且可以分化为不同类型的神经细胞，代替受损的细胞行使其功能。Parekkadan等^[6]的研究证实，移植的间充质干细胞对组织器官具有修复再生作用。Chang等^[7]的研究发现，移植的间充质干细胞能促进骨再生和修复。Ma等^[8]的临床研究证实，干细胞移植不但可以通过修复肝组织来抑制肝硬化发展，而且可以减少肝硬化转化为肝癌的风险。Taylor等^[9]的研究证实，干细胞移植能有效改善心肌梗死后的心肌功能。但有研究显示，干细胞移植并不能改善心肌功能。Von Lueder等^[10]提出心肌梗死后瘢痕组织形成导致的心功能持续恶化，是导致心肌干细胞移植治疗效果不能长期保持的原因之一。Neves 等^[11]的研究显示，移植间充质干细胞到宿主体内通过分泌神经生长因子、血管内皮生长因子、胰岛素生长因子、碱性成纤维细胞生长因子等多种营养因子，发挥营养神经作用。Kemp等^[12]的研究证实，体外或移植至体内的间充质干细胞，可以通过分泌超氧化物歧化酶发挥抗氧化作用。Ji等^[13]的研究显示，间充质干细胞植入到模型动物体内，会分布到各组织器官，而且不会引起组织细胞坏死。干细胞移植研究的进展，为治疗人类难治性疾病带来了希望。Zhang等^[14]的研究发现，骨髓间充质干细胞的神经分化潜能，为神经疾病的临床治疗带来了希望。Hao等^[15]的研究发现，神经干细胞移植后，在神经疾病动物模型脑组织内分化为神经细胞，改善了模型动物的受损神经功能。法国普瓦捷大学实验室和临床神经科学实验室与布鲁塞尔人类和分子生物学跨学科研究所合作，在成年小鼠的大脑皮质上进行移植胚胎干细胞实验，结果发现，这些多能性干细胞不但分化为皮质神经元，而且参与受损成年大脑回路的重建^[16]。加拿大英属哥伦比亚大学的研究人员将人体胚胎干细胞转化的胰腺祖细胞移植到2型糖尿病模型大鼠体内，结果发现这些移植细胞分化为能分泌胰岛素的β细胞，而且模型大鼠对胰岛素的敏感性和葡萄糖新陈代谢得到改善^[17]。目前，干细胞转化技术需要解决的一个问题是培养效率。只有达到高效率的培养，才能满足干细胞基础和临床研究的需要。干细胞调控机制的研究是干细胞转化基础研究中的一个重要的方面，与提高干细胞转化的效率和安全关系密切。现将干细胞转化技术及调控机制的研究进展做一个综述。