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

doi:10.3877/cma.j.issn.2095-1221.2022.03.006

Abstract

Abstract:

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

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.

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References 100

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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]
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	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]
CAD	-	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]
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	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]
MMD	SMCs；ECs	闭塞性脑血管疾病	大脑颈内动脉内膜增厚	RNF213 R4810k多态性	Hitomi等^[96]

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]
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	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]
CAD	-	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]
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	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]
MMD	SMCs；ECs	闭塞性脑血管疾病	大脑颈内动脉内膜增厚	RNF213 R4810k多态性	Hitomi等^[96]

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"

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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