MicroRNA调控耳蜗毛细胞发育的分子机制

饶琳，孟飞龙，房冉，蔡晨依，赵小立

MicroRNA调控耳蜗毛细胞发育的分子机制

饶琳，孟飞龙，房冉，蔡晨依，赵小立

浙江大学生命科学学院遗传与再生生物学研究所，浙江省细胞与基因工程重点研究实验室，杭州 310058

耳聋是严重影响人类生活质量的全球重大健康问题之一。目前，因耳蜗毛细胞损伤而导致的耳聋疾病尚未有成功的治疗方法。MicroRNA (miRNA)作为一类高度保守的内源性非编码小RNA，在耳蜗以及毛细胞发育过程中发挥着重要作用。本文介绍了miRNA在耳蜗毛细胞产生过程中的时空表达，揭示了其不可或缺的重要作用；同时阐述了miRNA参与调控耳蜗毛细胞发育中相关转录因子的分子机制，为耳聋的毛细胞移植治疗和毛细胞再生研究提供理论参考。

miRNA；耳蜗；听力损失；毛细胞

miRNA是一类高度保守的内源性非编码小RNA，通过抑制mRNA转录负调控靶基因的表达水平，从而参与调控细胞的生长发育、细胞信号转导、增殖分化、细胞凋亡、脂类代谢、蛋白质降解等过程[1]。1993年，在秀丽隐杆线虫()中最早发现miRNA基因lin-4[2]。它与lin-14 mRNA 3ʹ-UTR的碱基序列部分互补，通过降解靶基因lin-14参与调控线虫的生长发育[3]。随后越来越多的miRNA在植物、无脊椎动物和脊椎动物的组织中被发现[4]。近几年的研究发现miRNA在动物耳蜗的各类细胞中表达丰富[5]，已有研究表明miR-183家族在内耳毛细胞发育功能的调控中发挥了重要作用[6]。本文归纳总结了耳蜗毛细胞中主要miRNA的详细表达分布情况，并以miR-183家族的3个成员miR-96、miR-182和miR-183为主，分别阐述miRNA在内耳中的时空表达以及在内耳和毛细胞发育过程中参与调控的相关机制，旨在为进一步探索内耳毛细胞的发育分化、体外诱导及原位再生提供理论依据。

1 耳蜗中各类型细胞表达的miRNA

1.1 内耳的结构与功能

哺乳动物的耳是由外耳、中耳和内耳3个部分组成，内耳由负责感受声音的耳蜗和感受位置及运动觉的前庭器官组成[7]。耳蜗螺旋器(Corti器)坐落在基膜上，由感觉上皮(毛细胞)和支持细胞以及其他一些附属结构组成[8]。Corti器有3排外毛细胞(outer hair cell)和1排内毛细胞(inner ear hair cells)[9]。外毛细胞被称为“耳蜗放大器”，增强感觉上皮细胞对不同声音频率的响应能力，形成“机械—电—机械”的正反馈环路[10]。内毛细胞受到声音刺激，纤毛向外侧摆动，触发神经递质谷氨酸的释放，促使听神经传入冲动产生。声音冲动穿过传入神经到达耳蜗螺旋神经节(spiral ganglion)，进一步传到听觉中枢，传达到大脑产生听觉[11]。耳蜗膜性结构包括基膜、前庭膜和盖膜3个部分。基膜是上皮组织基底面与深部结缔组织之间的一层薄膜，给耳蜗部分提供韧性和质量，基膜与耳蜗螺旋韧带的蜗管相连形成一定的功能联系[12]。前庭膜起始于蜗轴侧的螺旋缘，与基底膜成45°，由两层细胞组成的一层薄膜，该膜可调节离子和液体平衡的作用[13]。

1.2 miRNA在耳蜗中的表达

miRNA与听觉功能密切相关，在耳蜗各类型的细胞中已经检测出超过100种miRNA[14]，如miR- 183、miR-96、miR-182、miR-124、miR-34a、miR-376和miR-135b等[15]。其中，miR-96、miR-182和miR-183等在小鼠和人的基因组中成簇排列，并且都是朝向同一方向转录生成，所以将这3种miRNA统称为miR-183基因簇或miR-183家族[16]。在毛细胞和螺旋神经节中的miRNA种类较多，已被证实的有miR-183家族、miR-15a、miR-30b、miR-99a、miR-18a、miR-140和miR-194等[17]。在内螺旋沟也检测到miR-96、miR-182和miR-183共3个miRNA，而在螺旋缘除了检测到miR-183家族的3个miRNA成员，还检测到miR-205表达[18]。同时，miR-205也存在于前庭膜和耳蜗螺旋韧带上[19]。基膜上除了存在miR-205a，此外还高表达miR-15a、miR-30b和miR-99a等miRNA[20]。但是支持细胞只有miR-15a、miR-30b和miR-99a表达[21]。边缘细胞中存在miR-376a和miR-376b，这些miRNA在内耳的其他部位中没有检测出来[22]。

除了上述提及的表达水平较高的miRNA，在已知成熟miRNA中有102种在耳蜗中表达，占全身miRNA总量的1/3[23]。组成耳蜗的细胞种类丰富，从miRNA的表达情况中可以看出一些组织和细胞存在着相同的miRNA[24]，比如毛细胞、螺旋神经节、螺旋缘、内螺旋沟等组织都有miR-96、miR-182和miR- 183的存在，前庭膜、螺旋缘、耳蜗螺旋韧带、基膜等组织则都表达了miR-205a[25]。这些结果为进一步掌握耳蜗的发育过程以及不同细胞组织之间的协同作用提供了研究依据[26]。在耳蜗中不同细胞和组织中主要高度表达的miRNA的表达情况如图1所示。

2 miRNA在耳蜗发育过程中的时空表达

2.1 内耳的发育过程

脊椎动物的内耳发育起源于胚胎的外胚层[27]。听泡(otic vesicle)又称耳囊(otic capsule)，起源于外胚层的听基板，在外胚层表面接近于神经板[28]。内耳的始基听泡发育产生于小鼠胚胎第8天(embryonic day 8, E8)至第11天，而人类在胚胎第4周末期才发育产生听泡[29]。在此发育阶段，内耳的平衡和听觉神经节也开始发育，该神经节是由内耳原始听泡的前腹内侧细胞从听泡分离并融合形成[30]。小鼠在E10.5~E14开始形成前庭和耳蜗，听泡脱离表面外胚层沉降到下方间充质内形成了听囊，听囊背侧发育为前庭部，而听囊腹侧发育为耳蜗部[31]。而感觉细胞的分化期，小鼠约在E13~E19，耳蜗上皮逐渐分化为感觉上皮，已有可分辨出的支持细胞和毛细胞[32]。出生时，前庭感觉器官发育已经接近于成熟，耳蜗已成型但体积比成熟期的耳蜗小[33]。出生后，前庭感觉器官、耳蜗逐渐发育成熟[34]，小鼠出生后第30天(postnatal day 30, P30)左右内耳器官完全发育成熟[35]。

图1 miRNA在耳蜗各类细胞中的表达

2.2 miRNA在动物模型耳蜗中的时空表达

miRNAs的表达呈现时间、空间及组织细胞的特异性[36]，表明其参与了组织的形态形成和细胞分化的过程[37]。由于人类的耳蜗组织不易获取，关于耳蜗miRNA的时空表达研究多局限于模式生物，再利用外推法来理解其在人类耳蜗中的具体功能[38]。在耳蜗领域最早进行研究的动物模型是小鼠，通过表达谱芯片分析小鼠耳蜗发育过程中不同时间点miRNA表达的状况[39]。在小鼠胚胎的整个发育过程中，miR-183和miR-182最早在胚胎期E9.5于听泡中表达。随着内耳在胚胎期的进一步发育，miR-183家族的3个成员在E11.5时出现表达差异，miR-182只有miR-182-5p表达，而在E12时miR-96、miR-182和miR-183呈现无差异表达，这可能反映了不同种类miRNA在内耳发育中的微小差异[40]。胚胎发育前期在miR-96、miR-182、miR-183听囊和螺旋神经节均有表达，E17.5时开始仅在毛细胞及其神经元中表达[41]。出生时(P0)，耳蜗毛细胞中检测到了miR-183家族、miR-15a*、miR-18a*、miR-30a*、miR-99a*、miR-199a*、miR-200*等诸多miRNAs的表达[42]。其中miR-183家族在小鼠出生后4-5天还存在于感觉前体细胞中，随后集中在耳蜗毛细胞呈现高度表达状态[43]。在P30时小鼠耳蜗已完全发育，此时在毛细胞中仍然可以检测到miR-183家族的表达[44]。从新生小鼠的耳蜗检测出的miRNA表达谱开始，经过听觉功能的发育和成熟，miRNA并没有发生实质性的改变，这表明miRNA的表达在很大程度上是在胚胎发育过程中建立起来的。从耳蜗发育的整个过程上看，miR-183、miR-96和miR-182的表达呈现出了时空组织的特异性，这种时间和空间上的表达与耳蜗的功能成熟密切相关[45]。miRNA家族时空表达的特异性见图2所示。

3 miR-183家族与毛细胞发育

3.1 毛细胞概述

人类内耳约有15 000个毛细胞，其中作为听觉感受器的耳蜗毛细胞约有3000个[46]。耳蜗毛细胞是分化成熟、高度特异性的终末细胞，哺乳动物毛细胞在出生后再生能力非常有限，听觉毛细胞损伤后很难分化形成新的毛细胞[47]。遗传或者获得性因素如年龄增长、耳毒性药物、病毒感染、噪音和外伤等都会使毛细胞受到损伤[48]，从而造成感音神经性耳聋(sensorineural hearing loss, SNHL)[49]。长期以来，感音神经性耳聋患者改善听力的选择仅仅限于助听器、人工耳蜗等设备，但这些方法无法从根本上解决问题[50]。因此，研究毛细胞的发育和再生的机制，可用于指导体外诱导干细胞分化为类毛细胞的研究，并通过细胞移植替换受损毛细胞，为治疗耳聋疾病带来新曙光[51]。

3.2 miR-183家族

目前在耳蜗毛细胞的miRNA研究中，miR-183家族的研究比较深入[52]。这个家族在进化过程中具有高度保守性，在结构上具有高度同源性(图3)。miR-183和miR-96之间有约1 kb的间隔区，miR-96和miR-182之间有约2.7~3.5 kb的间隔区。尽管3者之间的序列具有高度的相似性，但是其中微小的序列差异导致它们拥有不同的mRNA靶标。miR-183家族是最先被报道参与了纤毛化的感觉上皮细胞和神经纤毛细胞的器官发生和发育功能的基因簇[53]，它们在某些器官如眼睛、鼻子和内耳中有特殊的表达，对动物感觉器官的发育和功能的形成至关重要[54]。

3.2.1 miR-96

miR-96首先在人类癌细胞中被检测到，是miR-183家族中第一个被发现的miRNA成员[55]。miR-96是一种感觉器官特异性的miRNA，在哺乳动物耳蜗发育期间表达，可导致、和等重要发育基因表达下调。miR-96的种子区域的点突变会引起DNA序列多态性，导致人和小鼠常染色体显性非综合征性耳聋(non-syndromic hearing loss, NSHL)[56]。miR-96的种子序列第4个碱基G>A的突变，是第一个被发现的与遗传性耳聋相关的miRNA突变。Mencia等[57]从遗传性耳聋家系中证实+13G>A和+14C>A两个种子区域点突变也会影响成熟的miR-96与靶基因的结合效率，从而导致其对耳蜗毛细胞的调节失衡，最终引起了耳聋产生。Lewis等[58]利用强致癌剂N-亚硝基-N-乙基脲(N-ethyl-N-nitro­sourea, ENU)致小鼠听力损失，进一步对miR-96的种子区域点突变进行研究，发现有的突变体小鼠完全听力丧失并且毛细胞纤毛束不规则。Kuhn等[59]利用ENU小鼠突变体来探索miR-96在听觉器官发育至成熟过程中的作用机制，发现miR-96种子区域的突变影响了、和等内耳毛细胞相关靶基因的正常表达，毛细胞静纤毛束的成熟和耳蜗内听觉神经连接的重塑都会受到影响，进一步阐明了这一种子区域与听力损失有关[60]，miR-96可能与内耳毛细胞的静纤毛束的成熟和耳蜗神经的发育密切联系[61]。因此，了解miR-96的作用机制有助于进一步解释维持耳蜗正常活动所需基因的有序表达，并有助于深入研究非综合征性聋病发生的机制[62]。

图2 miR-183家族在小鼠耳蜗发育过程中表达的时间图

E为胚胎期，P为出生后。

图3 miR-183家族基因簇在人和小鼠中的染色体位置及种子序列

红色部分为microRNA种子系列。

3.2.2 miR-182

miR-182活性可能与靶基因有关，是一种参与毛细胞发育和分化的转录因子[63]。顺铂(cisplatin, CDDP)诱导的毛细胞凋亡前过表达miR-182，可抑制内源性凋亡途径的3个关键基因、和，从而保护耳蜗毛细胞免于细胞凋亡[64]。miR-182过表达会导致耳蜗毛细胞数量增加，在支持细胞中miR-182的低表达可抑制该细胞转分化为毛细胞。因此，在感觉细胞中过表达miR-182可以促进毛细胞再生，有望治疗由毛细胞丢失引起的感音神经性耳聋。Hildebrand等[65]利用隐性常染色体非综合征性耳聋人类家系，在()基因的3ʹ-UTR中发现了miR-182结合位点的C>A的纯合子突变。Wang等[66]将小鼠耳蜗干/祖细胞进行体外培养，发现过表达miR-182促进耳蜗干/祖细胞分化成毛细胞，此外，miR-182还与神经感觉器官、视觉感觉器官等器官的发育调控有关。在针对自闭症的全基因组研究中，Schellenberg等[67]在接近miR-182染色体位点的地方发现了这种疾病的易感基因，miR-182缺陷会导致自闭症的发生。Xu等[51]体外研究表明是miR-96和miR-182的直接靶点，是建立和维持视网膜发育和维持所必需的转录因子，miR-182的异常导致感觉器官发育程序的缺陷。

3.2.3 miR-183

miR-183能够调控耳蜗内毛细胞的发育分化及成熟的生理过程，miR-183可通过负调控其下游靶基因，使毛细胞的细胞骨架发生改变[68]。内耳在暴露于噪声28 d后miR-183、miR-96和miR-182的表达水平降低, 这与噪声导致外毛细胞的减少有关。在强烈的噪声刺激导致耳蜗毛细胞损伤后，miR-183可以通过抑制的表达来保护强刺激后受到损伤的耳蜗[69]。在体外培养的耳蜗螺旋器中，用吗啡反义寡核苷酸抑制miR-183的表达可导致Taok1蛋白增加并伴随耳蜗毛细胞的凋亡，说明miR-183在调节听觉创伤的耳蜗反应方面具有潜在的作用。Kim等[70]发现在新霉素诱导耳毒性斑马鱼中抑制miR-183表达，会降低毛细胞的再生，反之在斑马鱼胚胎中人工注射miR-183可以促进毛细胞正常发育。miR-183表达的变化先于动物形态学和功能的变化，在小鼠耳蜗发育的过程中，促进细胞增殖和分化的miR-183呈上调趋势，而在小鼠衰老时miR-183下调，促凋亡通路的调控因子miR-29家族和miR-34家族成员上调。

4 miRNA调控耳蜗发育的分子机制

4.1 miRNA与靶基因

人们对miRNA如何控制耳蜗发育的理解始于对突变体动物的研究。在斑马鱼模型中，幼体突变体的听觉器官严重畸形[71]。在小鼠中，基因在耳部早期发育时缺失，会导致内耳的整体尺寸减小，耳蜗生长受到严重阻碍[72]。基因在pre-miRNA加工成为成熟miRNA过程中至关重要，缺失严重影响了内耳的发育，间接地说明了miRNAs对耳蜗的重要性。miRNAs在耳蜗发育过程中参与调控重要基因的表达水平，从而参与了调控耳蜗细胞的增殖、迁移、发育和凋亡等过程。作为感觉前体细胞区域较早出现的标志之一，在人类耳蜗发育过程中的缺失引起了感音神经性耳聋，是内耳发育和毛细胞命运有关的转录因子，miR-182参与了靶基因和的表达调控[66]。miR-96的靶基因是和，其中是毛细胞成熟的重要基因[59]。此外，miR-96的靶基因还包括了渐进性耳聋的2个关键基因(表皮生长因子受体)和(神经营养因子受体)[55]。在其3'-UTR中包含一个高度保守的miR-96/-182结合位点,被认为是miR-96和miR-182的共同靶基因。Gu等[73]研究证实基因突变小鼠与ENU突变小鼠具有相似的立体纤毛形态，利用脂质体将miR-96和miR-182转染到耳蜗毛细胞中，可导致在mRNA水平和蛋白水平的表达量下降，进一步研究结果表明是由miR-96和miR-182直接调控的，确认靶序列位于3ʹ-UTR内的核苷760~766 bp之间。miR-183以为靶基因，通过抑制整合素α3的表达来控制耳蜗发育中的细胞增殖[71]。

除了上述的miR-183家族参与耳蜗发育的重要靶基因的调控，其他miRNA也在耳蜗发育过程中发挥重要作用。是负责产生透明软骨组分的基因，miR-9是的调控因子[72]。miR-124在耳蜗中的靶基因是Wnt信号通路的两个抑制因子和。miR-124于耳囊的神经上皮中高水平表达，促进神经细胞分化和轮廓形成[74]。miR-135b调控耳蜗中的转录激活因子[75]miR-194在耳蜗神经元和毛细胞中高度表达，通过调控和基因影响耳蜗神经细胞的分化[76]。内耳形态发生的关键调节因子是miR-200，在耳蜗和前庭上皮细胞中选择性表达，通过转录沉默和基因调控上皮–间质转化[77]。磷酸核糖焦磷酸合成酶1(PRPS1)的突变与一系列非综合征到综合征性听力损失有关，表达水平受miR-376的调控[78]。总之，这些miRNA以及其下游靶基因在耳蜗中组成了复杂的调控网络，共同调控耳蜗的发育过程[79]。有关miRNA调控耳蜗发育的靶基因见表1。

4.2 miRNA参与的信号通路

耳蜗前体细胞在耳蜗分化的过程中主要产生3种谱系的细胞，分别是神经前体细胞、感觉前体细胞和其它细胞[88]。神经细胞产生所必需的细胞因子是和，可以抑制和神经元的分化，而miR-182抑制的表达[89]。感觉细胞的产生时需要和等基因参与调控，细胞周期蛋白依赖性激酶(Cyclin-dependent kinase)抑制剂p27kip1，p19Ink4d和Rb抑制感觉细胞进入细胞周期，促进感觉前体细胞分化成毛细胞和支持细胞[90]毛细胞的形成和成熟需要和等细胞因子的调控[91]。Wnt信号通路[92]、Notch信号通路[93]、Shh信号通路[94]、FGF信号通路[95]和TGF信号通路[96]等信号通路参与了耳蜗的发育过程。其中，经典Wnt/β-catenin信号通路作用于耳蜗发育的最初阶段, 主要负责调控听囊和听基板的特化；而Wnt/PCP信号通路在哺乳动物的毛细胞静纤毛的生长排列和蜗管的延伸过程中发挥着重要作用[97]。miR-183家族可以通过抑制的表达，调控Wnt/β-catenin信号通路的传导[98]，而糖原合成酶激酶GSK3β通过Wnt/β-catenin /TCF/LEF-1信号通路影响miR-183家族的表达[99]。在哺乳动物发育过程中，Notch信号通路参与耳蜗感觉上皮的发育与分化过程，通过侧向抑制作用调控耳蜗感觉前体细胞向毛细胞的分化，从而确保内毛细胞至外毛细胞的正常分化顺序[100]。miR-384-5p转染细胞后，的表达水平显著下调[101]，miR-183通过抑制基因和从而抑制 Notch信号通路，参与毛细胞的分化和再生[102]。在耳蜗发育的早期阶段，FGF信号通路调控早期听基板的形成，在耳蜗发育后期，FGF信号分子主要参与毛细胞的发育，然而miRNA参与FGF信号通路调节的报道目前尚未见报道[103]。

表1 miRNA在耳蜗中的靶基因

miRNA在耳蜗发育过程中调节细胞凋亡方面还发挥了重要作用[104]。在电离辐射诱导的毛细胞死亡模型中，作为促凋亡因子的miR-207通过靶向基因(是PI3K/AKT途径等信号通路的关键基因)发挥了重要作用[105]。miR-182通过抑制PI3K AKT信号通路的直接靶点(促凋亡转录因子)的翻译来抑制细胞凋亡通路，可减轻毛细胞死亡[106]。miR-183通过抑制的表达,抑制诱导的细胞凋亡,调控TGF通路参与支持细胞和毛细胞的分化[107]。因此，通过下调和上调miRNA的表达来精准调控耳蜗干细胞的发育进程并减少毛细胞的凋亡是一种体内原位毛细胞再生的可行策略[108]。miRNA调控耳蜗发育的分子机制示意图见图4。

5 miRNA在治疗聋病方面应用前景

目前已有6000余个miRNA被找到，这些miRNA与生物体中约1/3的蛋白编码基因的调控密切相关[109]。miRNA已被证实是参与诸多内耳相关的病理发生过程的关键因素，如渐进性感音神经性耳聋、老年化耳聋、噪声性耳聋和内耳炎症等[110]。miRNA还参与了感觉毛细胞束发育、肌动蛋白重组、细胞粘附和内耳形态发生[111]。目前感音神经性耳聋治疗寄希望于毛细胞的移植治疗，细胞移植的关键是获得符合要求的毛细胞[90]。而获得毛细胞的唯一途径是来自于干细胞的体外诱导，所谓利用干细胞治疗感音神经性耳聋的最终目标是将干细胞诱导分化，再移植到毛细胞受损伤的部位作为替代细胞，达到重建损伤耳蜗并修复听力功能[112]。近年来一系列的研究表明胚胎干细胞、间充质干细胞、神经干细胞、内耳干细胞、iPS细胞等都可以在体外诱导分化为耳蜗类毛细胞[113]。然而，干细胞体外诱导获得的耳蜗类毛细胞虽然可以表达毛细胞相关的标志性蛋白，如Brn3c、Aoth1和MyosinⅦ等，但是扫描电镜观测到的类毛细胞的静纤毛和动纤毛仍与正常毛细胞的纤毛束有差距、神经电生理也有差异[114]。miRNA已经在毛囊细胞移植[115]、肝脏细胞体外分化[116]、心肌细胞体外分化[117]等方面有成功的案例。为此，本实验室构建过表达miR-183、miR-182和miR-96的载体导入到胚胎干细胞，利用这种胚胎干细胞研究体外诱导分化为毛细胞的机理，希望获得功能形态更加完整的毛细胞用于细胞移植治疗[37]。

图4 miRNA调控耳蜗发育的分子机制示意图

∣表示正调控；⊥表示负调控。

6 结语与展望

耳聋是全球性的疾病问题之一，世界上有5亿人遭受听力丧失的困扰，其中包括了3200万名儿童[118]。根据中国残联的最新数据显示：中国听力残疾的人数已达2780万人，听力残疾仅次于肢体残疾，是中国第二大致残疾病[119]。miRNA与耳蜗及毛细胞发育调控密切相关[120]，耳蜗中miRNA数量庞大，且一个miRNA可调控多个靶基因，多个miRNA也可协同调控一个靶基因，需要进一步明确与耳聋相关联的miRNA种类及生物特性。目前，miRNA在耳蜗中的具体分子机制尚未完全清楚，miRNA的成熟体究竟是在内耳的单个细胞内参与调控还是以外泌体等方式分泌到细胞外产生作用？内耳中表达了相同miRNA的细胞之间具有何种联系？miRNA参与调控内耳毛细胞纤毛束的具体作用方式是什么？这些问题都值得人们深入探讨。

另外，在耳蜗miRNA作用机理研究的基础上，将来可用小分子化合物和关键的miRNA共同导入到耳蜗诱导毛细胞的原位再生，也可以用外泌体作为载体负载miRNA或者使用miRNA拮抗剂，移植耳蜗诱导毛细胞的原位再生。这些以miRNA为基础的新技术，将为耳聋的治疗提供新的思路。

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Molecular mechanism of microRNA in regulating cochlear hair cell development

Lin Rao, Feilong Meng, Ran Fang, Chenyi Cai, Xiaoli Zhao

Deafness has become one of the most frequent health problems worldwide, and affects almost every age group. Hair cell damage or absence is the main cause of hearing loss, but there is no successful treatment to heal deafness. MicroRNA (miRNA), as a highly conserved endogenous non-coding small RNA, plays an important role in inner ear cochlea and hair cell development. In this review, we elaborate on the expression and function of miRNAs in cochlear hair cell development, and reveal its indispensable important role. We summarize the molecular mechanism of miRNA in regulating transcription factors involved in cochlear hair cell development, which may provide references and insights for hair cell regenerationand cellular transplantation therapy of deafness.

miRNA; cochlea; hearing loss; hair cells

2019-07-20;

2019-09-26

国家重点基础研究发展规划项目(973计划) (编号：2012CB967900)资助[Supported by the National Program on Key Basic Research Project (973 Program) (No. 2012CB967900)]

饶琳，硕士研究生，专业方向：干细胞分化。E-mail: 21707038@zju.edu.cn

赵小立，副教授，硕士生导师，研究方向：干细胞分化。E-mail: zhaoxiaoli@zju.edu.cn

10.16288/j.yczz.19-119

2019/10/29 16:01:28

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20191029.1042.003.html

(责任编委: 袁慧军)