饒琳，孟飛龍，房冉，蔡晨依，趙小立

MicroRNA調控耳蝸毛細胞發(fā)育的分子機制

饒琳，孟飛龍，房冉，蔡晨依，趙小立

浙江大學生命科學學院遺傳與再生生物學研究所，浙江省細胞與基因工程重點研究實驗室，杭州 310058

耳聾是嚴重影響人類生活質量的全球重大健康問題之一。目前，因耳蝸毛細胞損傷而導致的耳聾疾病尚未有成功的治療方法。MicroRNA (miRNA)作為一類高度保守的內源性非編碼小RNA，在耳蝸以及毛細胞發(fā)育過程中發(fā)揮著重要作用。本文介紹了miRNA在耳蝸毛細胞產生過程中的時空表達，揭示了其不可或缺的重要作用；同時闡述了miRNA參與調控耳蝸毛細胞發(fā)育中相關轉錄因子的分子機制，為耳聾的毛細胞移植治療和毛細胞再生研究提供理論參考。

miRNA；耳蝸；聽力損失；毛細胞

miRNA是一類高度保守的內源性非編碼小RNA，通過抑制mRNA轉錄負調控靶基因的表達水平，從而參與調控細胞的生長發(fā)育、細胞信號轉導、增殖分化、細胞凋亡、脂類代謝、蛋白質降解等過程[1]。1993年，在秀麗隱桿線蟲()中最早發(fā)現(xiàn)miRNA基因lin-4[2]。它與lin-14 mRNA 3?-UTR的堿基序列部分互補，通過降解靶基因lin-14參與調控線蟲的生長發(fā)育[3]。隨后越來越多的miRNA在植物、無脊椎動物和脊椎動物的組織中被發(fā)現(xiàn)[4]。近幾年的研究發(fā)現(xiàn)miRNA在動物耳蝸的各類細胞中表達豐富[5]，已有研究表明miR-183家族在內耳毛細胞發(fā)育功能的調控中發(fā)揮了重要作用[6]。本文歸納總結了耳蝸毛細胞中主要miRNA的詳細表達分布情況，并以miR-183家族的3個成員miR-96、miR-182和miR-183為主，分別闡述miRNA在內耳中的時空表達以及在內耳和毛細胞發(fā)育過程中參與調控的相關機制，旨在為進一步探索內耳毛細胞的發(fā)育分化、體外誘導及原位再生提供理論依據。

1 耳蝸中各類型細胞表達的miRNA

1.1 內耳的結構與功能

哺乳動物的耳是由外耳、中耳和內耳3個部分組成，內耳由負責感受聲音的耳蝸和感受位置及運動覺的前庭器官組成[7]。耳蝸螺旋器(Corti器)坐落在基膜上，由感覺上皮(毛細胞)和支持細胞以及其他一些附屬結構組成[8]。Corti器有3排外毛細胞(outer hair cell)和1排內毛細胞(inner ear hair cells)[9]。外毛細胞被稱為“耳蝸放大器”，增強感覺上皮細胞對不同聲音頻率的響應能力，形成“機械—電—機械”的正反饋環(huán)路[10]。內毛細胞受到聲音刺激，纖毛向外側擺動，觸發(fā)神經遞質谷氨酸的釋放，促使聽神經傳入沖動產生。聲音沖動穿過傳入神經到達耳蝸螺旋神經節(jié)(spiral ganglion)，進一步傳到聽覺中樞，傳達到大腦產生聽覺[11]。耳蝸膜性結構包括基膜、前庭膜和蓋膜3個部分?；な巧掀そM織基底面與深部結締組織之間的一層薄膜，給耳蝸部分提供韌性和質量，基膜與耳蝸螺旋韌帶的蝸管相連形成一定的功能聯(lián)系[12]。前庭膜起始于蝸軸側的螺旋緣，與基底膜成45°，由兩層細胞組成的一層薄膜，該膜可調節(jié)離子和液體平衡的作用[13]。

1.2 miRNA在耳蝸中的表達

miRNA與聽覺功能密切相關，在耳蝸各類型的細胞中已經檢測出超過100種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組中成簇排列，并且都是朝向同一方向轉錄生成，所以將這3種miRNA統(tǒng)稱為miR-183基因簇或miR-183家族[16]。在毛細胞和螺旋神經節(jié)中的miRNA種類較多，已被證實的有miR-183家族、miR-15a、miR-30b、miR-99a、miR-18a、miR-140和miR-194等[17]。在內螺旋溝也檢測到miR-96、miR-182和miR-183共3個miRNA，而在螺旋緣除了檢測到miR-183家族的3個miRNA成員，還檢測到miR-205表達[18]。同時，miR-205也存在于前庭膜和耳蝸螺旋韌帶上[19]。基膜上除了存在miR-205a，此外還高表達miR-15a、miR-30b和miR-99a等miRNA[20]。但是支持細胞只有miR-15a、miR-30b和miR-99a表達[21]。邊緣細胞中存在miR-376a和miR-376b，這些miRNA在內耳的其他部位中沒有檢測出來[22]。

除了上述提及的表達水平較高的miRNA，在已知成熟miRNA中有102種在耳蝸中表達，占全身miRNA總量的1/3[23]。組成耳蝸的細胞種類豐富，從miRNA的表達情況中可以看出一些組織和細胞存在著相同的miRNA[24]，比如毛細胞、螺旋神經節(jié)、螺旋緣、內螺旋溝等組織都有miR-96、miR-182和miR- 183的存在，前庭膜、螺旋緣、耳蝸螺旋韌帶、基膜等組織則都表達了miR-205a[25]。這些結果為進一步掌握耳蝸的發(fā)育過程以及不同細胞組織之間的協(xié)同作用提供了研究依據[26]。在耳蝸中不同細胞和組織中主要高度表達的miRNA的表達情況如圖1所示。

2 miRNA在耳蝸發(fā)育過程中的時空表達

2.1 內耳的發(fā)育過程

脊椎動物的內耳發(fā)育起源于胚胎的外胚層[27]。聽泡(otic vesicle)又稱耳囊(otic capsule)，起源于外胚層的聽基板，在外胚層表面接近于神經板[28]。內耳的始基聽泡發(fā)育產生于小鼠胚胎第8天(embryonic day 8, E8)至第11天，而人類在胚胎第4周末期才發(fā)育產生聽泡[29]。在此發(fā)育階段，內耳的平衡和聽覺神經節(jié)也開始發(fā)育，該神經節(jié)是由內耳原始聽泡的前腹內側細胞從聽泡分離并融合形成[30]。小鼠在E10.5~E14開始形成前庭和耳蝸，聽泡脫離表面外胚層沉降到下方間充質內形成了聽囊，聽囊背側發(fā)育為前庭部，而聽囊腹側發(fā)育為耳蝸部[31]。而感覺細胞的分化期，小鼠約在E13~E19，耳蝸上皮逐漸分化為感覺上皮，已有可分辨出的支持細胞和毛細胞[32]。出生時，前庭感覺器官發(fā)育已經接近于成熟，耳蝸已成型但體積比成熟期的耳蝸小[33]。出生后，前庭感覺器官、耳蝸逐漸發(fā)育成熟[34]，小鼠出生后第30天(postnatal day 30, P30)左右內耳器官完全發(fā)育成熟[35]。

圖1 miRNA在耳蝸各類細胞中的表達

2.2 miRNA在動物模型耳蝸中的時空表達

miRNAs的表達呈現(xiàn)時間、空間及組織細胞的特異性[36]，表明其參與了組織的形態(tài)形成和細胞分化的過程[37]。由于人類的耳蝸組織不易獲取，關于耳蝸miRNA的時空表達研究多局限于模式生物，再利用外推法來理解其在人類耳蝸中的具體功能[38]。在耳蝸領域最早進行研究的動物模型是小鼠，通過表達譜芯片分析小鼠耳蝸發(fā)育過程中不同時間點miRNA表達的狀況[39]。在小鼠胚胎的整個發(fā)育過程中，miR-183和miR-182最早在胚胎期E9.5于聽泡中表達。隨著內耳在胚胎期的進一步發(fā)育，miR-183家族的3個成員在E11.5時出現(xiàn)表達差異，miR-182只有miR-182-5p表達，而在E12時miR-96、miR-182和miR-183呈現(xiàn)無差異表達，這可能反映了不同種類miRNA在內耳發(fā)育中的微小差異[40]。胚胎發(fā)育前期在miR-96、miR-182、miR-183聽囊和螺旋神經節(jié)均有表達，E17.5時開始僅在毛細胞及其神經元中表達[41]。出生時(P0)，耳蝸毛細胞中檢測到了miR-183家族、miR-15a*、miR-18a*、miR-30a*、miR-99a*、miR-199a*、miR-200*等諸多miRNAs的表達[42]。其中miR-183家族在小鼠出生后4-5天還存在于感覺前體細胞中，隨后集中在耳蝸毛細胞呈現(xiàn)高度表達狀態(tài)[43]。在P30時小鼠耳蝸已完全發(fā)育，此時在毛細胞中仍然可以檢測到miR-183家族的表達[44]。從新生小鼠的耳蝸檢測出的miRNA表達譜開始，經過聽覺功能的發(fā)育和成熟，miRNA并沒有發(fā)生實質性的改變，這表明miRNA的表達在很大程度上是在胚胎發(fā)育過程中建立起來的。從耳蝸發(fā)育的整個過程上看，miR-183、miR-96和miR-182的表達呈現(xiàn)出了時空組織的特異性，這種時間和空間上的表達與耳蝸的功能成熟密切相關[45]。miRNA家族時空表達的特異性見圖2所示。

3 miR-183家族與毛細胞發(fā)育

3.1 毛細胞概述

人類內耳約有15 000個毛細胞，其中作為聽覺感受器的耳蝸毛細胞約有3000個[46]。耳蝸毛細胞是分化成熟、高度特異性的終末細胞，哺乳動物毛細胞在出生后再生能力非常有限，聽覺毛細胞損傷后很難分化形成新的毛細胞[47]。遺傳或者獲得性因素如年齡增長、耳毒性藥物、病毒感染、噪音和外傷等都會使毛細胞受到損傷[48]，從而造成感音神經性耳聾(sensorineural hearing loss, SNHL)[49]。長期以來，感音神經性耳聾患者改善聽力的選擇僅僅限于助聽器、人工耳蝸等設備，但這些方法無法從根本上解決問題[50]。因此，研究毛細胞的發(fā)育和再生的機制，可用于指導體外誘導干細胞分化為類毛細胞的研究，并通過細胞移植替換受損毛細胞，為治療耳聾疾病帶來新曙光[51]。

3.2 miR-183家族

目前在耳蝸毛細胞的miRNA研究中，miR-183家族的研究比較深入[52]。這個家族在進化過程中具有高度保守性，在結構上具有高度同源性(圖3)。miR-183和miR-96之間有約1 kb的間隔區(qū)，miR-96和miR-182之間有約2.7~3.5 kb的間隔區(qū)。盡管3者之間的序列具有高度的相似性，但是其中微小的序列差異導致它們擁有不同的mRNA靶標。miR-183家族是最先被報道參與了纖毛化的感覺上皮細胞和神經纖毛細胞的器官發(fā)生和發(fā)育功能的基因簇[53]，它們在某些器官如眼睛、鼻子和內耳中有特殊的表達，對動物感覺器官的發(fā)育和功能的形成至關重要[54]。

3.2.1 miR-96

miR-96首先在人類癌細胞中被檢測到，是miR-183家族中第一個被發(fā)現(xiàn)的miRNA成員[55]。miR-96是一種感覺器官特異性的miRNA，在哺乳動物耳蝸發(fā)育期間表達，可導致、和等重要發(fā)育基因表達下調。miR-96的種子區(qū)域的點突變會引起DNA序列多態(tài)性，導致人和小鼠常染色體顯性非綜合征性耳聾(non-syndromic hearing loss, NSHL)[56]。miR-96的種子序列第4個堿基G>A的突變，是第一個被發(fā)現(xiàn)的與遺傳性耳聾相關的miRNA突變。Mencia等[57]從遺傳性耳聾家系中證實+13G>A和+14C>A兩個種子區(qū)域點突變也會影響成熟的miR-96與靶基因的結合效率，從而導致其對耳蝸毛細胞的調節(jié)失衡，最終引起了耳聾產生。Lewis等[58]利用強致癌劑N-亞硝基-N-乙基脲(N-ethyl-N-nitro-sourea, ENU)致小鼠聽力損失，進一步對miR-96的種子區(qū)域點突變進行研究，發(fā)現(xiàn)有的突變體小鼠完全聽力喪失并且毛細胞纖毛束不規(guī)則。Kuhn等[59]利用ENU小鼠突變體來探索miR-96在聽覺器官發(fā)育至成熟過程中的作用機制，發(fā)現(xiàn)miR-96種子區(qū)域的突變影響了、和等內耳毛細胞相關靶基因的正常表達，毛細胞靜纖毛束的成熟和耳蝸內聽覺神經連接的重塑都會受到影響，進一步闡明了這一種子區(qū)域與聽力損失有關[60]，miR-96可能與內耳毛細胞的靜纖毛束的成熟和耳蝸神經的發(fā)育密切聯(lián)系[61]。因此，了解miR-96的作用機制有助于進一步解釋維持耳蝸正?；顒铀杌虻挠行虮磉_，并有助于深入研究非綜合征性聾病發(fā)生的機制[62]。

圖2 miR-183家族在小鼠耳蝸發(fā)育過程中表達的時間圖

E為胚胎期，P為出生后。

圖3 miR-183家族基因簇在人和小鼠中的染色體位置及種子序列

紅色部分為microRNA種子系列。

3.2.2 miR-182

miR-182活性可能與靶基因有關，是一種參與毛細胞發(fā)育和分化的轉錄因子[63]。順鉑(cisplatin, CDDP)誘導的毛細胞凋亡前過表達miR-182，可抑制內源性凋亡途徑的3個關鍵基因、和，從而保護耳蝸毛細胞免于細胞凋亡[64]。miR-182過表達會導致耳蝸毛細胞數(shù)量增加，在支持細胞中miR-182的低表達可抑制該細胞轉分化為毛細胞。因此，在感覺細胞中過表達miR-182可以促進毛細胞再生，有望治療由毛細胞丟失引起的感音神經性耳聾。Hildebrand等[65]利用隱性常染色體非綜合征性耳聾人類家系，在()基因的3?-UTR中發(fā)現(xiàn)了miR-182結合位點的C>A的純合子突變。Wang等[66]將小鼠耳蝸干/祖細胞進行體外培養(yǎng)，發(fā)現(xiàn)過表達miR-182促進耳蝸干/祖細胞分化成毛細胞，此外，miR-182還與神經感覺器官、視覺感覺器官等器官的發(fā)育調控有關。在針對自閉癥的全基因組研究中，Schellenberg等[67]在接近miR-182染色體位點的地方發(fā)現(xiàn)了這種疾病的易感基因，miR-182缺陷會導致自閉癥的發(fā)生。Xu等[51]體外研究表明是miR-96和miR-182的直接靶點，是建立和維持視網膜發(fā)育和維持所必需的轉錄因子，miR-182的異常導致感覺器官發(fā)育程序的缺陷。

3.2.3 miR-183

miR-183能夠調控耳蝸內毛細胞的發(fā)育分化及成熟的生理過程，miR-183可通過負調控其下游靶基因，使毛細胞的細胞骨架發(fā)生改變[68]。內耳在暴露于噪聲28 d后miR-183、miR-96和miR-182的表達水平降低, 這與噪聲導致外毛細胞的減少有關。在強烈的噪聲刺激導致耳蝸毛細胞損傷后，miR-183可以通過抑制的表達來保護強刺激后受到損傷的耳蝸[69]。在體外培養(yǎng)的耳蝸螺旋器中，用嗎啡反義寡核苷酸抑制miR-183的表達可導致Taok1蛋白增加并伴隨耳蝸毛細胞的凋亡，說明miR-183在調節(jié)聽覺創(chuàng)傷的耳蝸反應方面具有潛在的作用。Kim等[70]發(fā)現(xiàn)在新霉素誘導耳毒性斑馬魚中抑制miR-183表達，會降低毛細胞的再生，反之在斑馬魚胚胎中人工注射miR-183可以促進毛細胞正常發(fā)育。miR-183表達的變化先于動物形態(tài)學和功能的變化，在小鼠耳蝸發(fā)育的過程中，促進細胞增殖和分化的miR-183呈上調趨勢，而在小鼠衰老時miR-183下調，促凋亡通路的調控因子miR-29家族和miR-34家族成員上調。

4 miRNA調控耳蝸發(fā)育的分子機制

4.1 miRNA與靶基因

人們對miRNA如何控制耳蝸發(fā)育的理解始于對突變體動物的研究。在斑馬魚模型中，幼體突變體的聽覺器官嚴重畸形[71]。在小鼠中，基因在耳部早期發(fā)育時缺失，會導致內耳的整體尺寸減小，耳蝸生長受到嚴重阻礙[72]?；蛟趐re-miRNA加工成為成熟miRNA過程中至關重要，缺失嚴重影響了內耳的發(fā)育，間接地說明了miRNAs對耳蝸的重要性。miRNAs在耳蝸發(fā)育過程中參與調控重要基因的表達水平，從而參與了調控耳蝸細胞的增殖、遷移、發(fā)育和凋亡等過程。作為感覺前體細胞區(qū)域較早出現(xiàn)的標志之一，在人類耳蝸發(fā)育過程中的缺失引起了感音神經性耳聾，是內耳發(fā)育和毛細胞命運有關的轉錄因子，miR-182參與了靶基因和的表達調控[66]。miR-96的靶基因是和，其中是毛細胞成熟的重要基因[59]。此外，miR-96的靶基因還包括了漸進性耳聾的2個關鍵基因(表皮生長因子受體)和(神經營養(yǎng)因子受體)[55]。在其3'-UTR中包含一個高度保守的miR-96/-182結合位點,被認為是miR-96和miR-182的共同靶基因。Gu等[73]研究證實基因突變小鼠與ENU突變小鼠具有相似的立體纖毛形態(tài)，利用脂質體將miR-96和miR-182轉染到耳蝸毛細胞中，可導致在mRNA水平和蛋白水平的表達量下降，進一步研究結果表明是由miR-96和miR-182直接調控的，確認靶序列位于3?-UTR內的核苷760~766 bp之間。miR-183以為靶基因，通過抑制整合素α3的表達來控制耳蝸發(fā)育中的細胞增殖[71]。

除了上述的miR-183家族參與耳蝸發(fā)育的重要靶基因的調控，其他miRNA也在耳蝸發(fā)育過程中發(fā)揮重要作用。是負責產生透明軟骨組分的基因，miR-9是的調控因子[72]。miR-124在耳蝸中的靶基因是Wnt信號通路的兩個抑制因子和。miR-124于耳囊的神經上皮中高水平表達，促進神經細胞分化和輪廓形成[74]。miR-135b調控耳蝸中的轉錄激活因子[75]miR-194在耳蝸神經元和毛細胞中高度表達，通過調控和基因影響耳蝸神經細胞的分化[76]。內耳形態(tài)發(fā)生的關鍵調節(jié)因子是miR-200，在耳蝸和前庭上皮細胞中選擇性表達，通過轉錄沉默和基因調控上皮–間質轉化[77]。磷酸核糖焦磷酸合成酶1(PRPS1)的突變與一系列非綜合征到綜合征性聽力損失有關，表達水平受miR-376的調控[78]?？傊?，這些miRNA以及其下游靶基因在耳蝸中組成了復雜的調控網絡，共同調控耳蝸的發(fā)育過程[79]。有關miRNA調控耳蝸發(fā)育的靶基因見表1。

4.2 miRNA參與的信號通路

耳蝸前體細胞在耳蝸分化的過程中主要產生3種譜系的細胞，分別是神經前體細胞、感覺前體細胞和其它細胞[88]。神經細胞產生所必需的細胞因子是和，可以抑制和神經元的分化，而miR-182抑制的表達[89]。感覺細胞的產生時需要和等基因參與調控，細胞周期蛋白依賴性激酶(Cyclin-dependent kinase)抑制劑p27kip1，p19Ink4d和Rb抑制感覺細胞進入細胞周期，促進感覺前體細胞分化成毛細胞和支持細胞[90]毛細胞的形成和成熟需要和等細胞因子的調控[91]。Wnt信號通路[92]、Notch信號通路[93]、Shh信號通路[94]、FGF信號通路[95]和TGF信號通路[96]等信號通路參與了耳蝸的發(fā)育過程。其中，經典Wnt/β-catenin信號通路作用于耳蝸發(fā)育的最初階段, 主要負責調控聽囊和聽基板的特化；而Wnt/PCP信號通路在哺乳動物的毛細胞靜纖毛的生長排列和蝸管的延伸過程中發(fā)揮著重要作用[97]。miR-183家族可以通過抑制的表達，調控Wnt/β-catenin信號通路的傳導[98]，而糖原合成酶激酶GSK3β通過Wnt/β-catenin /TCF/LEF-1信號通路影響miR-183家族的表達[99]。在哺乳動物發(fā)育過程中，Notch信號通路參與耳蝸感覺上皮的發(fā)育與分化過程，通過側向抑制作用調控耳蝸感覺前體細胞向毛細胞的分化，從而確保內毛細胞至外毛細胞的正常分化順序[100]。miR-384-5p轉染細胞后，的表達水平顯著下調[101]，miR-183通過抑制基因和從而抑制 Notch信號通路，參與毛細胞的分化和再生[102]。在耳蝸發(fā)育的早期階段，F(xiàn)GF信號通路調控早期聽基板的形成，在耳蝸發(fā)育后期，F(xiàn)GF信號分子主要參與毛細胞的發(fā)育，然而miRNA參與FGF信號通路調節(jié)的報道目前尚未見報道[103]。

表1 miRNA在耳蝸中的靶基因

miRNA在耳蝸發(fā)育過程中調節(jié)細胞凋亡方面還發(fā)揮了重要作用[104]。在電離輻射誘導的毛細胞死亡模型中，作為促凋亡因子的miR-207通過靶向基因(是PI3K/AKT途徑等信號通路的關鍵基因)發(fā)揮了重要作用[105]。miR-182通過抑制PI3K AKT信號通路的直接靶點(促凋亡轉錄因子)的翻譯來抑制細胞凋亡通路，可減輕毛細胞死亡[106]。miR-183通過抑制的表達,抑制誘導的細胞凋亡,調控TGF通路參與支持細胞和毛細胞的分化[107]。因此，通過下調和上調miRNA的表達來精準調控耳蝸干細胞的發(fā)育進程并減少毛細胞的凋亡是一種體內原位毛細胞再生的可行策略[108]。miRNA調控耳蝸發(fā)育的分子機制示意圖見圖4。

5 miRNA在治療聾病方面應用前景

目前已有6000余個miRNA被找到，這些miRNA與生物體中約1/3的蛋白編碼基因的調控密切相關[109]。miRNA已被證實是參與諸多內耳相關的病理發(fā)生過程的關鍵因素，如漸進性感音神經性耳聾、老年化耳聾、噪聲性耳聾和內耳炎癥等[110]。miRNA還參與了感覺毛細胞束發(fā)育、肌動蛋白重組、細胞粘附和內耳形態(tài)發(fā)生[111]。目前感音神經性耳聾治療寄希望于毛細胞的移植治療，細胞移植的關鍵是獲得符合要求的毛細胞[90]。而獲得毛細胞的唯一途徑是來自于干細胞的體外誘導，所謂利用干細胞治療感音神經性耳聾的最終目標是將干細胞誘導分化，再移植到毛細胞受損傷的部位作為替代細胞，達到重建損傷耳蝸并修復聽力功能[112]。近年來一系列的研究表明胚胎干細胞、間充質干細胞、神經干細胞、內耳干細胞、iPS細胞等都可以在體外誘導分化為耳蝸類毛細胞[113]。然而，干細胞體外誘導獲得的耳蝸類毛細胞雖然可以表達毛細胞相關的標志性蛋白，如Brn3c、Aoth1和MyosinⅦ等，但是掃描電鏡觀測到的類毛細胞的靜纖毛和動纖毛仍與正常毛細胞的纖毛束有差距、神經電生理也有差異[114]。miRNA已經在毛囊細胞移植[115]、肝臟細胞體外分化[116]、心肌細胞體外分化[117]等方面有成功的案例。為此，本實驗室構建過表達miR-183、miR-182和miR-96的載體導入到胚胎干細胞，利用這種胚胎干細胞研究體外誘導分化為毛細胞的機理，希望獲得功能形態(tài)更加完整的毛細胞用于細胞移植治療[37]。

圖4 miRNA調控耳蝸發(fā)育的分子機制示意圖

∣表示正調控；⊥表示負調控。

6 結語與展望

耳聾是全球性的疾病問題之一，世界上有5億人遭受聽力喪失的困擾，其中包括了3200萬名兒童[118]。根據中國殘聯(lián)的最新數(shù)據顯示：中國聽力殘疾的人數(shù)已達2780萬人，聽力殘疾僅次于肢體殘疾，是中國第二大致殘疾病[119]。miRNA與耳蝸及毛細胞發(fā)育調控密切相關[120]，耳蝸中miRNA數(shù)量龐大，且一個miRNA可調控多個靶基因，多個miRNA也可協(xié)同調控一個靶基因，需要進一步明確與耳聾相關聯(lián)的miRNA種類及生物特性。目前，miRNA在耳蝸中的具體分子機制尚未完全清楚，miRNA的成熟體究竟是在內耳的單個細胞內參與調控還是以外泌體等方式分泌到細胞外產生作用？內耳中表達了相同miRNA的細胞之間具有何種聯(lián)系？miRNA參與調控內耳毛細胞纖毛束的具體作用方式是什么？這些問題都值得人們深入探討。

另外，在耳蝸miRNA作用機理研究的基礎上，將來可用小分子化合物和關鍵的miRNA共同導入到耳蝸誘導毛細胞的原位再生，也可以用外泌體作為載體負載miRNA或者使用miRNA拮抗劑，移植耳蝸誘導毛細胞的原位再生。這些以miRNA為基礎的新技術，將為耳聾的治療提供新的思路。

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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

國家重點基礎研究發(fā)展規(guī)劃項目(973計劃) (編號：2012CB967900)資助[Supported by the National Program on Key Basic Research Project (973 Program) (No. 2012CB967900)]

饒琳，碩士研究生，專業(yè)方向：干細胞分化。E-mail: 21707038@zju.edu.cn

趙小立，副教授，碩士生導師，研究方向：干細胞分化。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

(責任編委: 袁慧軍)