干细胞心肌分化调控过程中的非编码RNA

doi:10.3877/cma.j.issn.2095-1221.2022.05.007

心血管疾病（CVDs）是目前我国城乡居民死亡的首要原因。尽管目前的医疗手段可以改善症状并减缓不良心脏重构，但未能解决心脏组织不可逆损失的根本问题。干细胞在适当的条件诱导下可以定向分化为心肌细胞，应用多能干细胞来源的心肌细胞（PSC-CMs）修复受损心脏以恢复正常心功能是一种理想的治疗手段。在干细胞向心肌细胞分化的过程中，多种转录因子和信号通路遵循一定规律在不同时间节点的表达，对此进行调控可提高PSC-CMs的获取效率。在过去十余年中，对非编码RNA （ncRNA）特别是微小RNA （miRNA）、长链非编码RNA （lncRNA）和环状RNA （circRNA）作为基因表达调控的关键分子已经得到了大量研究，其生物学调控的作用主要体现在表观遗传学、转录和转录后水平。心脏的发育过程同样受到ncRNA的调节，本文综述了在心肌细胞分化和成熟过程中ncRNA的调控机制，为更有效地获取高质量的PSC-CMs，将其用于CVDs的临床治疗提供理论指导。

关键词: 干细胞, 心肌细胞, 分化, 非编码RNA

Cardiovascular diseases (CVDs) are currently the leading cause of death in China. Although current medical interventions can alleviate symptoms and reduce adverse cardiac remodeling, they fail to address the underlying problem of irreversible loss of cardiac tissue. Under certain conditions, stem cells can directionally differentiate into cardiomyocytes. And it is an ideal way to restore normal heart function by treating impaired hearts with pluripotent stem cell-derived cardiomyocytes (PSC-CMs) . During the differentiation of stem cells into cardiomyocytes, multiple transcription factors and signaling pathways follow a certain pattern of expression at different periods, which can be regulated to improve the efficiency of harvesting PSC-CMs. In the last decade or so, the role of non-coding RNA (ncRNA) , especially microRNA (miRNA) , long non-coding RNA (lncRNA) and circular RNA (circRNA) , as critical molecules in the regulation of gene expression, has been extensively investigated. The biological regulatory functions of ncRNAs occur at the epigenetic level and during transcriptional and post-transcriptional levels. The development of the heart is also regulated by ncRNAs. In this review, we outlined the regulatory mechanisms of ncRNAs during cardiomyocyte differentiation and maturation to provide theoretical guidance for more effective acquisition of high-quality PSC-CMs to be used in the clinical treatment of CVDs.

Key words: Stem cells, Cardiomyocytes, Differentiation, non-coding RNA

表1 诱导干细胞心肌分化的miRNA

名称	作用靶点	生物学作用	对心肌分化的调节	参考文献
miR-148a	DMNT1	抑制心脏特异性蛋白GATA-4甲基化	促进分化	[39，40]
miR-19b	Wnt1	协同5-aza促进BMSCs向心肌样细胞分化促进细胞增殖、分化、抑制凋亡抑制Wnt/β-catenin信号通路	促进分化	[41，45]
miR-149	Dab2	负调节Dab2，解除Dab2对Wnt/β-catenin信号通路的抑制作用	促进分化	[13]
miR-1-2	Wnt11	增强非经典Wnt通路增加心脏特异性基因表达	促进分化	[14]
miR-499		增加心脏特异性基因的表达激活Wnt/β-catenin信号通路	促进分化	[15]
miR-26b	Gsk3β和Wnt5a	促进细胞增殖、分化、抑制凋亡抑制Wnt5a和Gsk3β的表达，激活经典Wnt信号通路，抑制非经典Wnt信号通路	促进分化	[46]
miR-335-3p，miR-335-5p	DKK1 SMAD7	激活Wnt信号通路激活TGF-β信号通路	促进分化	[47]
miR-184	Wnt3	抑制经典Wnt信号通路	早期抑制分化，后期促进分化	[48]
miR-1	FZD7，FRS2 Hes-1	抑制Wnt信号通路和FGF信号通路抑制ESCs衍生的多能心血管祖细胞向血管内皮细胞系定型负调控Hes-1促进心脏特异性基因表达	促进分化	[49，57]
miR-375	Notch2	抑制Notch2影响Notch通路促进细胞凋亡，抑制增殖	抑制分化	[53]
miR-148a，miR-1a	Dll1	抑制Dll1介导的Notch信号通路	促进分化	[55，56]
miR-199b-5p	HSF1 HSP70	HSF1/HSP70信号通路	抑制分化	[58]
miR-124	STAT3	下调STAT3，减少心脏特异性标志物的表达	抑制分化	[59]
miR-98-5p，miR-10-5p	TBX5	下调TBX5，减少心肌相关的基因mRNA表达	抑制分化	[60，61]

表1 诱导干细胞心肌分化的miRNA

名称	作用靶点	生物学作用	对心肌分化的调节	参考文献
miR-148a	DMNT1	抑制心脏特异性蛋白GATA-4甲基化	促进分化	[39，40]
miR-19b	Wnt1	协同5-aza促进BMSCs向心肌样细胞分化促进细胞增殖、分化、抑制凋亡抑制Wnt/β-catenin信号通路	促进分化	[41，45]
miR-149	Dab2	负调节Dab2，解除Dab2对Wnt/β-catenin信号通路的抑制作用	促进分化	[13]
miR-1-2	Wnt11	增强非经典Wnt通路增加心脏特异性基因表达	促进分化	[14]
miR-499		增加心脏特异性基因的表达激活Wnt/β-catenin信号通路	促进分化	[15]
miR-26b	Gsk3β和Wnt5a	促进细胞增殖、分化、抑制凋亡抑制Wnt5a和Gsk3β的表达，激活经典Wnt信号通路，抑制非经典Wnt信号通路	促进分化	[46]
miR-335-3p，miR-335-5p	DKK1 SMAD7	激活Wnt信号通路激活TGF-β信号通路	促进分化	[47]
miR-184	Wnt3	抑制经典Wnt信号通路	早期抑制分化，后期促进分化	[48]
miR-1	FZD7，FRS2 Hes-1	抑制Wnt信号通路和FGF信号通路抑制ESCs衍生的多能心血管祖细胞向血管内皮细胞系定型负调控Hes-1促进心脏特异性基因表达	促进分化	[49，57]
miR-375	Notch2	抑制Notch2影响Notch通路促进细胞凋亡，抑制增殖	抑制分化	[53]
miR-148a，miR-1a	Dll1	抑制Dll1介导的Notch信号通路	促进分化	[55，56]
miR-199b-5p	HSF1 HSP70	HSF1/HSP70信号通路	抑制分化	[58]
miR-124	STAT3	下调STAT3，减少心脏特异性标志物的表达	抑制分化	[59]
miR-98-5p，miR-10-5p	TBX5	下调TBX5，减少心肌相关的基因mRNA表达	抑制分化	[60，61]

表2 诱导干细胞心肌分化的lncRNA

名称	作用靶点	生物学作用	对心肌分化的调节	参考文献
lncRNA Braveheart （Bvht）	Mesp1	心脏特异性转录因子和上皮细胞-间充质转化（EMT）相关基因的表达上调	促进分化	[63，64]
lncRNA Cpmer	eEF1A2	与翻译伸长因子eEF1A2相互作用并特异性识别并Eomes mRNA翻译	促进分化	[65]
lincRNA 1405	Eomes	linc1405与Eomes结合，调节下游Mesp1	促进分化	[66]
lncRNA CARMEN	SUZ12 EZH2	分化早期直接参与早期谱系定型，控制多能性和心脏中胚层指定基因的表达	促进分化	[67]
lncRNA Moshe	Nkx2.5	将第二生心区（secondaryheart filed）相关基因Isl-1的表达控制在适当的水平	促进分化	[68]
lncRNA SNHG6	miR-101	激活Wnt/β-catenin通路	促进分化	[69]
lncRNA GATA6-AS1	GATA6	调节中胚层标志物表达调控经典和非经典Wnt信号通路的时间表达	促进分化	[70]
lncRNA C20orf166-AS1 （CARMA）	miR-1 miR-133a2	负调节miR1和miR-133a2 调节下游Notch受体Notch1，Notch2以及配体Jag1，Jag2抑制Notch信号通路影响CARMA水平，形成调节心脏生成的正调节循环	抑制分化	[71]
lncRNA HBL1	miR-1	负调控miR-1	抑制分化	[72]
lncRNA RCPCD	DNMT	增加启动子区域HCN4的甲基化水平抑制HCN4的表达	抑制分化	[73]
PPP1R1B-lncRNA	Tbx5	影响心肌细胞的成肌分化	促进分化	[74]

表2 诱导干细胞心肌分化的lncRNA

名称	作用靶点	生物学作用	对心肌分化的调节	参考文献
lncRNA Braveheart （Bvht）	Mesp1	心脏特异性转录因子和上皮细胞-间充质转化（EMT）相关基因的表达上调	促进分化	[63，64]
lncRNA Cpmer	eEF1A2	与翻译伸长因子eEF1A2相互作用并特异性识别并Eomes mRNA翻译	促进分化	[65]
lincRNA 1405	Eomes	linc1405与Eomes结合，调节下游Mesp1	促进分化	[66]
lncRNA CARMEN	SUZ12 EZH2	分化早期直接参与早期谱系定型，控制多能性和心脏中胚层指定基因的表达	促进分化	[67]
lncRNA Moshe	Nkx2.5	将第二生心区（secondaryheart filed）相关基因Isl-1的表达控制在适当的水平	促进分化	[68]
lncRNA SNHG6	miR-101	激活Wnt/β-catenin通路	促进分化	[69]
lncRNA GATA6-AS1	GATA6	调节中胚层标志物表达调控经典和非经典Wnt信号通路的时间表达	促进分化	[70]
lncRNA C20orf166-AS1 （CARMA）	miR-1 miR-133a2	负调节miR1和miR-133a2 调节下游Notch受体Notch1，Notch2以及配体Jag1，Jag2抑制Notch信号通路影响CARMA水平，形成调节心脏生成的正调节循环	抑制分化	[71]
lncRNA HBL1	miR-1	负调控miR-1	抑制分化	[72]
lncRNA RCPCD	DNMT	增加启动子区域HCN4的甲基化水平抑制HCN4的表达	抑制分化	[73]
PPP1R1B-lncRNA	Tbx5	影响心肌细胞的成肌分化	促进分化	[74]

表3 诱导干细胞心肌分化的circRNA

名称	作用靶点	生物学作用	对心肌分化的调节	参考文献
circFOXP1	miR-17-3p miR-127-5p	下调的circFOXP1增强经典Wnt信号通路，抑制非经典Wnt信号通路	抑制分化	[80]
circRNA_0000804（circRCCD）	转录因子YY1	负调控MyD88基因表达	促进分化	[82]
circRNA_105039	miR-17	抑制miR-17对cyclinD2转录的调节	促进分化	[84]

表3 诱导干细胞心肌分化的circRNA

名称	作用靶点	生物学作用	对心肌分化的调节	参考文献
circFOXP1	miR-17-3p miR-127-5p	下调的circFOXP1增强经典Wnt信号通路，抑制非经典Wnt信号通路	抑制分化	[80]
circRNA_0000804（circRCCD）	转录因子YY1	负调控MyD88基因表达	促进分化	[82]
circRNA_105039	miR-17	抑制miR-17对cyclinD2转录的调节	促进分化	[84]

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Non-coding RNAs in the regulation of myocardial differentiation in stem cells

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Non-coding RNAs in the regulation of myocardial differentiation in stem cells