Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (1): 101-105.doi: 10.12307/2022.017
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Cui Shuaishuai1, Yang Xiaohong2
Received:
2021-01-27
Revised:
2021-01-29
Accepted:
2021-03-16
Online:
2022-01-08
Published:
2021-10-25
Contact:
Yang Xiaohong, PhD, Professor, Department of Prosthodontics, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
About author:
Cui Shuaishuai, Master candidate, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
Supported by:
CLC Number:
Cui Shuaishuai, Yang Xiaohong. Effects of miRNA in self-renewal, multidirectional differentiation, fate and function regulation of bone marrow mesenchymal stem cells [J]. Chinese Journal of Tissue Engineering Research, 2022, 26(1): 101-105.
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2.1 骨髓间充质干细胞概述 骨骼代谢的稳态对骨骼健康至关重要。骨质疏松、骨关节炎和骨折等骨病主要是骨骼系统自我更新过程(称为骨骼重塑)失败引起的,而该过程包括成骨细胞介导的骨形成和破骨细胞介导的骨吸收[1],其中成骨细胞来源于骨髓间充质干细胞,而破骨细胞来源于造血干细胞[2]。骨髓间充质干细胞是来源于中胚层的多能干细胞[3],在特定条件下可以分化为成骨细胞、成软骨细胞、上皮细胞、心肌细胞和肝细胞等[4],因此已在急性肺损伤、心肌梗死以及肝肾衰竭等不同临床前疾病模型中得到应用并显示出良好的效果[3]。已有研究表明随着年龄的增长,骨髓间充质干细胞的成骨作用减慢,骨形成减少、骨折风险增加以及骨髓脂肪增多[5],因此加深对骨髓间充质干细胞成骨分化、成脂分化分子机制的认识,是制定骨质疏松等系统性骨代谢疾病治疗策略的先决条件。 2.2 miRNA概述 miRNA是一类高度保守的组织特异性非小蛋白非编码RNA[6],具有通过识别同源序列以及抑制mRNA翻译或促进mRNA降解在转录后水平调节基因表达的能力[7-8]。 miRNA广泛参与细胞的发育、增殖、分化和凋亡[9],并且多种生理过程和病理结果高度依赖于miRNA[8]。据推测,miRNA 调控了1/3人类基因,并参与了一些重要的生命过程[10]。因此,近年来miRNA 逐渐成为生命科学研究领域的热点。大量研究证实miRNA在骨代谢过程中发挥了极其重要的调控作用,参与维持骨代谢的平衡。miRNA在调节骨髓间充质干细胞向特定谱系分化中起着关键作用[11]。文章对miRNA调控骨髓间充质干细胞增殖及不同谱系定向分化的作用作一综述。 2.3 miRNA对骨髓间充质干细胞生物学特性的影响 2.3.1 miRNA对骨髓间充质干细胞增殖的影响 基于骨髓间充质干细胞的再生疗法对于颅面缺损重建至关重要[12],虽然骨髓间充质干细胞已被用于口腔颌面部缺损的治疗,但其有限的增殖能力降低了骨髓间充质干细胞的治疗效率[13]。因此,骨髓间充质干细胞的体外扩增成为干细胞研究与组织再生领域亟需解决的问题,近年来,研究人员通过对miRNA的微观干预调控骨髓间充质干细胞增殖取得了一定的进展。例如XIAOLING等[14]研究发现,绝经后骨质疏松患者骨髓间充质干细胞中LncRNA H19明显下调,转染H19通过下调 miR-19b-3p显著降低骨髓间充质干细胞增殖和分化。Li等[15]实验发现,黄芩多糖下调了miR-152的表达,抑制miR-152表达对骨髓间充质干细胞的增殖和分化表现出促进作用,而转染miR-152模拟物则一定程度上抑制了骨髓间充质干细胞的增殖及分化。骨形态发生蛋白9是miR-152的直接靶标,并参与介导骨髓间充质干细胞中miR-152的功能,骨形态发生蛋白9激活骨髓间充质干细胞中的PI3K/AKT和Wnt/β-catenin信号通路,从而增强了骨髓间充质干细胞的增殖和分化。DAI等[16]研究发现,与股骨颈骨骨折患者相比,类固醇相关性骨坏死患者的骨髓间充质干细胞中miR-217表达水平显著降低,miR-217通过靶向DKK1,促进β-catenin核易位,增加RUNX2、COL1A1的表达,明显促进骨髓间充质干细胞的增殖。KONG等[17]研究表明,miR-146a可以促进骨髓间充质干细胞的增殖。LV等[18]研究表明,转染agomiR-103导致miR-103过表达抑制了骨髓间充质干细胞增殖和成骨分化,而antagomiR-103使miR-103沉默则消除了这些抑制作用,进一步的研究表明,SATB2是miR-103的直接靶基因,转染agomiR-103的骨髓间充质干细胞显著下调了SATB2的蛋白表达水平;MA等[13]研究表明,miR-31可以激活CXCR4/Akt途径,而CXCR4/Akt信号阻断可以消除miR-31对骨髓间充质干细胞增殖、存活和迁移的有益作用;Zhang等[19]研究发现,miR-15a-5p过表达通过Wnt /β-catenin/PPAR信号通路促进骨髓间充质干细胞的凋亡并减少细胞的增殖。通过多位学者的探索研究,研究发现miRNA对骨髓间充质干细胞的增殖、迁移有着不可或缺的调控作用,这为未来骨髓间充质干细胞的临床应用奠定了坚实的基础。 2.3.2 miRNA对骨髓间充质干细胞成骨分化的调控 一些miRNA已被证明通过调节与骨髓间充质干细胞成骨分化相关的基因来促进其分化。例如,糖皮质激素广泛用于治疗慢性炎症性疾病,但长期应用糖皮质激素可导致骨质疏松,LI等[20]学者通过使用地塞米松诱导骨髓间充质干细胞模拟糖皮质激素性骨质疏松症的方法来探索miR-291a-3p影响骨髓间充质干细胞分化的机制,结果发现,miR-291a-3p可提高骨髓间充质干细胞的细胞活力、成骨分化能力和碱性磷酸酶活性,而这三者均受到地塞米松的抑制;与此同时,在转染miRNA-291a-3p模拟物后,成骨基因Runx2、DMP1和ALP表达上调,而脂肪生成基因C/EBPα和PPARγ表达下调,进一步研究发现miR-291a-3p可通过直接抑制DKK1 mRNA和蛋白的表达,进而激活Wnt/β-catenin信号通路,从而促进骨髓间充质干细胞的成骨分化,这一发现提示miR-291a-3p在预防骨质疏松症中发挥重要作用。ZHAO等[21]学者发现在过表达miR -21的骨髓间充质干细胞中,HIF-1α和p-Akt蛋白表达上调,当加入PI3K抑制剂后,p-Akt和HIF-1α蛋白表达下调,同时他们也进行了体内实验,将miR-21修饰的骨髓间充质干细胞/β-磷酸三钙复合材料植入大鼠骨缺损模型,通过 Micro-CT、荧光标记和组织形态学分析,发现miR-21显著增加了骨缺损部位的新骨形成和矿化,该研究说明miR-21 通过增加HIF-1α和p-Akt活性以及PTEN降解来促进骨髓间充质干细胞成骨分化,从而显著增加大鼠骨缺损部位新骨形成。LI等[22]研究发现,褪黑激素具有调节骨髓间充质干细胞成骨分化的能力,褪黑激素作用后骨髓间充质干细胞中miR-92b-5P的表达上调,转染miR-92b-5P可促进骨髓间充质干细胞的成骨分化,miR-92b-5P沉默可抑制骨髓间充质干细胞的成骨作用,进一步通过荧光素酶报告基因分析、实时qPCR分析和western blot分析证实miR-92b-5P通过直接靶向细胞内黏附分子1参与成骨过程,该研究结果表明褪黑素可提高miR-92b-5P的表达,miR-92b-5P可靶向细胞内黏附分子1调控骨髓间充质干细胞向成骨细胞分化,为骨质疏松症的治疗提供了新的方法。CHEN等[23]研究发现miR-136-3p在乙醇诱导的骨质减少小鼠模型中显著下调,下调miR-136-3p表达显著抑制了人脐静脉内皮细胞和骨髓间充质干细胞的血管形成和成骨分化,而miR-136-3p Agomir改善了乙醇诱导的骨质减少,同时恢复了骨量和血管形成,该研究首次证实了miR-136-3p/PTEN轴在调控血管形成和骨形成中的关键作用,可能成为酒精性骨丢失的潜在治疗靶点。随着miRNA不断深入研究,越来越多的miRNA被发现在骨髓间充质干细胞的成骨分化中起着不可或缺的作用,miR-217、miR-106a、 miR-26a、miR-199b-5p等均被发现可以促进骨髓间充质干细胞向成骨细胞分化,促进骨再生[16,24-26]。 除了上述几种miRNA发挥促进成骨分化的作用外,一些miRNA过表达还会抑制成骨细胞分化,使骨质疏松症、牙周病等骨相关疾病难以愈合。例如,FENG等[27]研究发现,骨质疏松症大鼠骨髓间充质干细胞中miR-139-5p的表达增加,抑制miR-139-5p通过NOTCH1靶向Wnt/β-catenin信号传导途径促进骨髓间充质干细胞的成骨分化;LI等[28]研究发现,与对照组相比,再生障碍性贫血患者的骨髓间充质干细胞中miR-144-3p显著上调,而miR-144-3p缺失可显著增强再生障碍性贫血患者骨髓间充质干细胞成骨分化,相反,过表达miR-144-3p阻碍了骨髓间充质干细胞的成骨分化, miR-144-3p负向调控骨髓间充质干细胞中TET2的表达,TET2表达降低与总5-羟甲基胞嘧啶水平和成骨基因表达显著降低相关,miR-144-3p通过抑制TET2的表达降低再生障碍性贫血患者骨髓间充质干细胞的成骨能力,因此,靶向miR-144-3p可能是治疗再生障碍性贫血的一种策略。1型糖尿病是一种自身免疫性胰岛素依赖性疾病,与破坏骨稳态有关,WANG等[29]利用miRNA芯片筛选差异表达的miRNA,发现miR-214-3p可能抑制1型糖尿病小鼠骨髓间充质干细胞分化,通过分子研究发现miR-214-3p通过靶向β-catenin的 3'-UTR抑制骨髓间充质干细胞成骨分化,这一研究表明 miR-214-3p可能是治疗1型糖尿病患者骨骼疾病的一个潜在靶点。正畸治疗期间周期性拉伸诱导的骨骼形成是一个复杂的生物过程,受多种因素调节。LIU等[30]学者使用miRNA芯片技术筛选拉伸诱导骨髓间充质干细胞成骨分化过程中机械敏感的miRNA,并鉴定出9个差异表达miRNA,选择其中显著下调的miR-503-5p用于进一步功能验证。研究发现,在骨髓间充质干细胞中过表达miR-503-5p可减弱拉伸诱导的成骨分化,而抑制miR-503-5p可逆转这一作用。除了上述几种抑制骨髓间充质干细胞成骨分化的miRNA,近年来越来越多的miRNA被发现可以抑制骨髓间充质干细胞的成骨分化,例如miR-99a,miR-449b-5p,miR-205,miR-384-5p等均可以通过不同的信号通路,靶向不同目的基因抑制骨髓间充质干细胞向成骨细胞分化[31-34]。 2.3.3 miRNA对骨髓间充质干细胞成脂分化的调控 骨髓间充质干细胞具有分化为不同细胞谱系的能力,而干细胞分化程序对于骨骼微环境和骨骼发育至关重要,在骨髓间充质干细胞的成骨分化方面学者们已经有了大量的研究,而骨髓间充质干细胞的成脂分化对于骨代谢的平衡同样不可忽视。近年来,关于骨髓间充质干细胞的成脂分化同样有学者进行了重要的探索。例如,在猪骨髓间充质干细胞被化学诱导分化为脂肪细胞的过程中miR-17,miR-21和miR-143的表达增加,然后,miR-17,miR-21和miR-143模拟物的过表达增加了脂肪细胞分化的油红O阳性细胞的数量,表明miR-17,miR-21和miR-143参与并促进猪骨髓间充质干细胞的成脂分化[35];ZHAO等[36]研究表明,三氧化二砷治疗再生障碍性贫血患者具有临床疗效,再生障碍性贫血患者的骨髓间充质干细胞易于被诱导成脂肪细胞而不是成骨细胞,三氧化二砷治疗可以至少部分恢复骨髓间充质干细胞的分化失衡,miR-204在这一过程起关键作用,下调miR-204表达可能是治疗再生障碍性贫血的新策略。ZHANG等[37]研究发现老年2型糖尿病并发骨质疏松症患者的骨组织和血清中miR-205表达增加,而miR-205的过表达抑制了2型糖尿病并发骨质疏松症老年雌性小鼠骨髓间充质干细胞的成骨分化并促进其成脂分化,miR-205的敲低则促进成骨分化并抑制其成脂分化。ZHU等[38] 通过双重荧光素酶报告基因测定发现Klf3是miR-20a-5p的直接靶标,siRNA介导的Klf3沉默增强了miR-20a-5p过表达诱导的脂肪生成作用,而Klf3的表达增强则减弱了miR-20a-5p 的作用,这一结果表明miR-20a-5p是通过在脂肪形成过程的早期阶段靶向并负调控Klf3来促进骨髓间充质干细胞向脂肪细胞分化。QIU等[39]研究发现,miR-214-5p可能通过调节TGF/Smad2/COL4A1信号通路来促进骨髓间充质干细胞的成脂分化。上述已被证实的miRNA对骨髓间充质干细胞成脂分化能力具有正向促进作用,同样有些miRNA对骨髓间充质干细胞的成脂分化能力具有负向抑制作用。例如, miR-149-3p过表达通过与FTO mRNA的3'UTR结合而抑制了肥胖相关基因的表达,这对于调节体质量和脂肪质量起着重要作用[11];GU等[40]在类固醇引起的股骨头坏死大鼠模型中鉴定了9个上调的miRNA和28个下调的miRNA,其中miR-27a 被下调并与PPAR和GREM1表达负相关,通过进一步研究证实,PPAR和GREM1是miR-27a的直接靶标,而miR-27a下调增强了成脂分化,而miR-27a上调则减弱了类固醇诱导的大鼠骨髓间充质干细胞的脂肪形成并促进成骨。 2.3.4 miRNA对骨髓间充质干细胞成软骨分化的调控 骨髓间充质干细胞的软骨分化对于软骨再生至关重要,但是其分化机制仍然不甚明了,近年来学者们对这一问题做出了关键的探索。例如,WON等[41]研究发现,载有miR-140的外泌体在骨髓间充质干细胞分化为软骨细胞中发挥生物活性作用,参与软骨愈合过程。LI等[42]研究发现,软骨细胞衍生的外泌体miR-8485通过调控Wnt/β-catenin途径,促进骨髓间充质干细胞的软骨分化,为软骨重建提供了创新思路。CHEN等[43]通过实验发现,循环拉伸应变可以促进miR-365的表达,miR-365是参与骨髓间充质干细胞软骨形成的关键机械敏感miRNA,直接抑制HDAC4的表达,进而增强骨髓间充质干细胞的软骨形成。WU等[44]学者发现褪黑素通过上调miR-526b-3p和miR-590-5p从而促进人骨髓间充质干细胞的软骨分化,这一功能是通过靶向SMAD7增强SMAD1磷酸化实现的,此外,miR-526b-3p模拟物或miR-590-5p模拟物也成功地促进了人骨髓间充质干细胞的软骨分化,这一研究结果表明,使用褪黑激素或miRNA转导修饰骨髓间充质干细胞可能是治疗软骨损伤和变性的有效方法。XUE等[45] 通过研究证实,miR-127-5p通过增加Sox9的表达和降低Runx2的表达,可以促进大鼠骨髓间充质干细胞的软骨分化和减少软骨肥大。ZHANG等[46]研究发现,在转化生长因子3诱导骨髓间充质干细胞软骨分化过程中miR-410的表达升高,miR-410转染增加了软骨生成标记物(Ⅱ型胶原蛋白、Sox9、聚集蛋白聚糖和透明质酸合酶2)的mRNA和蛋白表达水平,降低Wnt3a蛋白表达,证实了miR-410是骨髓间充质干细胞软骨分化的关键调控因子,直接靶向触发Wnt信号通路的Wnt3a。然而,也有学者发现部分miRNA抑制了骨髓间充质干细胞的成软骨分化。例如,TIAN等[47]研究发现,在软骨分化过程中miR-143-3p表达水平降低,而且 miR-143-3p可以通过靶向骨髓间充质干细胞中的BMPR2来调控分化过程;CHEN等[48]研究表明,miR-485-5p可以降低SOX9表达水平,促进软骨表面炎性因子的产生,并阻止小鼠骨髓间充质干细胞向软骨细胞分化。 2.3.5 miRNA对骨髓间充质干细胞向其他谱系分化的调控 骨髓间充质干细胞在特定条件下可以分化为心肌细胞和肝细胞等,其中miRNA同样承担不可或缺的角色。例如,HE等[49] 研究表明,过表达GATA-4的骨髓间充质干细胞来源外泌体诱导骨髓间充质干细胞分化为心肌样细胞,减少缺氧诱导的心肌细胞凋亡,并改善梗死后的心肌功能;DAI等[50]研究发现,miR-199b-5p表达下调通过HSF1/ HSP70信号通路诱导骨髓间充质干细胞向心肌样细胞分化,而对骨髓间充质干细胞的增殖和迁移没有影响;YAN等[51]研究发现,在衰老的肝脏中miR-126a表达减少,而骨髓间充质干细胞中miR-126a减少引起年龄相关的端粒缩短、DNA损伤反应和促炎细胞因子增多。 近年来,随着miRNA在生命科学领域的不断深入研究,越来越多的miRNA被发现在骨髓间充质干细胞增殖及不同谱系分化中起着重要的调控作用,这些特异性miRNA可能成为靶向药物治疗的有用靶点,见表1。 "
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