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中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2022, Vol. 12 ›› Issue (03) : 167 -175. doi: 10.3877/cma.j.issn.2095-1221.2022.03.006

综述

人诱导多能干细胞及其在血管相关疾病模型中的应用
胡敏洁1, 王思贤1, 王永煜1,†()   
  1. 1. 325035　温州，浙江省温州医科大学基础医学院
  • 收稿日期:2022-03-15 出版日期:2022-06-01
  • 通信作者: 王永煜
  • 基金资助:
    国家自然科学基金(82070487，81670454); 浙江省自然科学基金(LY21C120003)

Human induced pluripotent stem cell and its applications in vascular disease modeling

Minjie Hu1, Sixian Wang1, Yongyu Wang1,†()   

  1. 1. College of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China
  • Received:2022-03-15 Published:2022-06-01
  • Corresponding author: Yongyu Wang
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胡敏洁, 王思贤, 王永煜. 人诱导多能干细胞及其在血管相关疾病模型中的应用[J]. 中华细胞与干细胞杂志(电子版), 2022, 12(03): 167-175.

Minjie Hu, Sixian Wang, Yongyu Wang. Human induced pluripotent stem cell and its applications in vascular disease modeling[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2022, 12(03): 167-175.

诱导多能干细胞（iPSCs）是由体细胞重编程获得的一种与胚胎干细胞类似能够无限自我更新和分化成体内各种细胞类型的多能干细胞。iPSCs现已广泛应用于人类疾病的发病机制研究、治疗药物研发及再生医学等领域。血管疾病具有较高的发病率和死亡率，其发病机制常与血管平滑肌细胞（VSMCs）和内皮细胞（ECs）功能障碍有关。建立血管疾病特异性iPSCs并将其定向分化为VSMCs和ECs等，可作为研究血管疾病发病机制或进行药物筛选的重要体外细胞模型。此外，3D培养和其他技术的发展应用还可从3D水平模拟体内环境将iPSCs应用于疾病模型构建和发病机制研究。本综述旨在介绍血管疾病特异性iPSCs的获取、iPSCs定向诱导分化为SMCs和ECs的方法及其在各种血管疾病发病机制研究中的应用与挑战。

关键词: 诱导多能干细胞, 重编程, 血管平滑肌细胞, 内皮细胞, 分化, 3D模型, 疾病模型

Induced pluripotent stem cells (iPSCs) are reprogrammed from somatic cells, which is similar to embryonic stem cells with the capable of infinite self-renewal and differentiation into various types of cells. The iPSCs have been widely used in the pathogenesis of human disease modeling, drug development and regenerative medicine. Vascular diseases with high morbidity and mortality are often associated with the dysfunction of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) . Establishment of patient-specific iPSCs and the derived-SMCs or ECs can provide an important cellular model for studying the pathogenesis of vascular diseases, as well as drug screening. In addition, the development and application of 3-Dimensions (3D) culture and other technologies can also simulate to generate the 3D constructs, such as organoid, organ on chip, and disease modeling. The purpose of this review is to introduce the generation of iPSCs, the differentiation methods of SMCs and ECs from iPSCs, as well as their applications and challenges in the pathogenesis of the various vascular diseases.

Key words: iPSCs, Reprogramming, SMCs, EC, Differentiation, 3D models, Disease modeling
图1 iPSC重编程、定向分化为SMCs和ECs及其在各种血管相关疾病模型中的应用注：OCT4、SOX2、NANOG、KLF4为重编程关键转录因子；CRISPR为成簇的规律间隔的短回文重复序列；iPSCs为诱导多能干细胞；2D为二维；3D为三维；iPSC为诱导多能干细胞；SMCs为平滑肌细胞；ECs为内皮细胞
表1 iPSCs诱导的SMCs在血管疾病模型中的应用
疾病 病变细胞 特征 表型 突变基因 参考文献
HGPS SMCs 血管早衰、动脉粥样硬化、中风 VSMCs丢失 LMNA基因突变 Pitrez等[74]；Liu等[34]
MFS SMCs 结缔组织疾病，多个器官出现病理，胸主动脉受影响最为明显 FBN1沉积；ECM降解；收缩和凋亡缺陷 15q21.1 c.6388G > A （p.E2130K） Li等[80]
c.4082G > A Klein等[81]
外显子21 c.2638G> A；外显子30（c.3725G > A） Granata等[25]
PRKG1中的c.530G> A突变（p.Arg177Gln） Shalhub等[82]
FBN1 c.2939G > A Qin等[4]
FBN1 c.6734G > A Pan等[83]
FBN1c.2613A > C，（p.Leu871Phe）和c.684_736 + 4del Ma等[84]
BS - 先天性蛛网膜炎、漏斗胸、脊柱侧凸、TAD FBN2突变 FBN2基因c.728 T > C Liu等[85]
WBS SMCs 主动脉发育不良和认知障碍 对血管活性激动剂，卡巴胆碱和内皮素-1的反应降低；血管形成受损；钙通量降低 7q11.23半合子缺失 Ghaffari等[86]；Kinnear等[30]
SVAS SMCs 血管狭窄 VSMCs异常增殖 ELN基因突变 Kinnear等[24]
CADASIL SMCs 遗传性脑血管疾病 细胞骨架解体；细胞过度增殖 NOTCH3基因突变 Ling等[5]
LDS SMCs 多发性骨折，腭裂，广泛的动脉瘤和动脉弯曲 SMCs收缩功能减弱，增殖能力增强；ECM形成破坏 TGFBR1A230T突变；TGFBR1外显子4 （p.M253I; c.759G > A） Zhou等[11]；Pongpamorn等[87]
TGFBR2突变 Hu等[88]
TAA/TAD SMCs 进行性主动脉根部扩张、夹层、破裂 VSMCs收缩性减弱 SMAD3突变 Gong等[89]
COL4A2突变 Jin等[90]
NOTCH1缺乏 Abudupataer等[75]
CAD SMCs 血管钙化 SMCs增殖和迁移能力增加 9p21.3基因座 Lo Sardo等[7]；Trillhaase等[35]
- 原因不明的冠状动脉疾病，肌纤维发育不良 - 与PHACTR1/EDN1基因有关 Mishra等[91]
BAV SMCs；ECs 三尖瓣的两小叶异常融合的主动脉瓣缺陷性疾病，常与TAA/TAD相关 SMCs收缩减弱，线粒体功能障碍，EC间质转化 NOTCH1基因突变 Jiao等[32,92]
ROBO4基因突变 Dong等[93]
糖尿病 SMCs；ECs 血糖升高，心血管疾病，微血管病变，糖尿病足 SMCs脂质代谢异常，引起动脉粥样硬化 芳基乙酰胺脱乙酰酶表达发生改变 Toyohara等[36]
异常血管生成 - Chan等[94]
伤口难以愈合 - Gorecka等[95]
MMD SMCs；ECs 闭塞性脑血管疾病 大脑颈内动脉内膜增厚 - Tokairin等[37]
RNF213 R4810k多态性 Hitomi等[96]
表2 iPSCs诱导的ECs在血管疾病模型中的应用
疾病 病变细胞 特征 表型 突变基因 参考文献
HGPS ECs 血管早衰、动脉粥样硬化、中风 ECs功能障碍 LMNA基因突变 Mojiri等[43]；Atchison等[65]
PAH ECs 肺血管床逐渐破坏，继发右心室压力增加，心力衰竭 细胞的粘附、存活率和迁移率降低，血管生成减少 BMPR2杂合突变 Gu等[42]
DGS ECs 精神分裂、BBB功能失调 BBB的溶质渗透性增加，跨内皮电阻降低 第22号染色体q11.2带微缺失 Li等[45]
HD ECs 神经变性显性疾病 血管生成增多；屏障功能降低；WNT/β-catenin通路表达上调 HTT基因外显子1中的CAG重复扩增 Lim等[39]
COVID-19 ECs 全身性血管炎 ECs炎症激活和功能障碍 ACE2表达增加 Ma等[48]；Yang等[50]
ESRD ECs 肾功能进行性下降 ECs功能障碍 - Kim等[51]；Roye等[73]
BAV ECs 见"表1 BAV"
糖尿病 ECs 见"表1糖尿病"
MMD ECs 见"表1 MMD"
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