鞏朝陽(yáng)，劉開(kāi)鑫，向高，張海鴻

蘭州大學(xué)第二醫(yī)院骨科，甘肅蘭州市730030

脊髓損傷是一種常見(jiàn)且具有破壞性的中樞神經(jīng)系統(tǒng)(central nervous system,CNS)損傷性疾病，會(huì)引起不可逆的運(yùn)動(dòng)和感覺(jué)功能障礙，以及膀胱、腸道和性功能的喪失，導(dǎo)致生活質(zhì)量顯著降低。對(duì)于脊髓損傷后的治療，目前依然沒(méi)有確切有效的治療方案。病理上，在嚴(yán)重脊髓損傷后，由于局部微環(huán)境的變化，星形膠質(zhì)細(xì)胞轉(zhuǎn)化為反應(yīng)性星形膠質(zhì)細(xì)胞并發(fā)生劇烈的形態(tài)變化，與脊髓中的其他細(xì)胞一起參與膠質(zhì)瘢痕的形成[1]。脊髓損傷后期膠質(zhì)瘢痕的形成被大多數(shù)學(xué)者認(rèn)為是阻礙哺乳動(dòng)物CNS軸突再生和功能恢復(fù)的主要原因，膠質(zhì)瘢痕中反應(yīng)性星形膠質(zhì)細(xì)胞產(chǎn)生的硫酸軟骨素和硫酸角質(zhì)素蛋白聚糖是產(chǎn)生抑制性作用的主要分子。對(duì)膠質(zhì)瘢痕的研究可能是將來(lái)治療脊髓損傷的另一個(gè)重要方向。本文就脊髓損傷后膠質(zhì)瘢痕的形成及相關(guān)作用進(jìn)行綜述。

1 膠質(zhì)瘢痕細(xì)胞來(lái)源

創(chuàng)傷性脊髓損傷會(huì)使病灶區(qū)域形成瘢痕組織，包括纖維化瘢痕和膠質(zhì)瘢痕[2]。膠質(zhì)瘢痕的形成通常被稱(chēng)為反應(yīng)性星形膠質(zhì)細(xì)胞增生，包括星形膠質(zhì)細(xì)胞肥大、增殖、遷移以及星形膠質(zhì)細(xì)胞表達(dá)的膠質(zhì)纖維酸性蛋白(glial fibrillary acidic protein,GFAP)、波形蛋白和巢蛋白的上調(diào)增加[3]。輕度星形膠質(zhì)細(xì)胞增生通常不會(huì)發(fā)生顯著的增殖活動(dòng)，這種類(lèi)型的反應(yīng)被稱(chēng)為“同構(gòu)性膠質(zhì)增生”，可見(jiàn)于化學(xué)損傷、軸突切開(kāi)術(shù)或輕度損傷。這些變化可以通過(guò)減弱上游信號(hào)分子的觸發(fā)效應(yīng)來(lái)逆轉(zhuǎn)[4-5]。嚴(yán)重脊髓損傷后，隨著時(shí)間的推移，反應(yīng)性星形膠質(zhì)細(xì)胞表現(xiàn)出強(qiáng)烈的GFAP表達(dá)、明顯的肥大和一定程度的增殖，這些顯著變化導(dǎo)致星形膠質(zhì)細(xì)胞個(gè)別區(qū)域的破壞并導(dǎo)致組織變形，還伴隨明顯的星形膠質(zhì)細(xì)胞增殖。在此階段，形成包圍脊髓損傷中心的膠質(zhì)瘢痕[6]。形成膠質(zhì)瘢痕的星形膠質(zhì)細(xì)胞主要有兩個(gè)來(lái)源。一是接近于病變區(qū)近端對(duì)細(xì)胞骨架蛋白有明顯上調(diào)作用，形成新的具有干細(xì)胞特性的星形膠質(zhì)細(xì)胞祖細(xì)胞[7]。在急性脊髓損傷后的數(shù)小時(shí)內(nèi)，Zhao等[8]發(fā)現(xiàn)許多增殖的膠質(zhì)祖細(xì)胞與GFAP+的星形膠質(zhì)細(xì)胞共同表達(dá)神經(jīng)膠質(zhì)抗原2(neuron-glial antigen 2,NG2)，這表明NG2+的祖細(xì)胞可能是反應(yīng)性星形膠質(zhì)細(xì)胞的一個(gè)來(lái)源。二是從遠(yuǎn)端區(qū)域遷移到病灶部位的星形膠質(zhì)細(xì)胞[9]。

星形膠質(zhì)細(xì)胞是最豐富的神經(jīng)膠質(zhì)細(xì)胞，在CNS中扮演著重要的角色。生理狀態(tài)下，在發(fā)育和成人CNS中，參與處理、轉(zhuǎn)移及存儲(chǔ)神經(jīng)元信息、引導(dǎo)神經(jīng)元的發(fā)育、遷移及分化，介導(dǎo)突觸功能及可塑性，參與血脊柱屏障的形成及維護(hù)和提供能量等[10-13]。脊髓損傷后，星形膠質(zhì)細(xì)胞的活化及反應(yīng)性膠質(zhì)細(xì)胞增生參與神經(jīng)可塑性和CNS再生的各個(gè)方面[14-15]。

2 反應(yīng)性星形膠質(zhì)細(xì)胞增生的信號(hào)機(jī)制

脊髓損傷后膠質(zhì)瘢痕形成的相關(guān)分子機(jī)制尚未完全闡明，星形膠質(zhì)細(xì)胞參與膠質(zhì)瘢痕形成涉及多個(gè)過(guò)程。本文僅介紹有關(guān)反應(yīng)性星形膠質(zhì)細(xì)胞增生的信號(hào)機(jī)制。

2.1 結(jié)構(gòu)蛋白的上調(diào)及介導(dǎo)星形膠質(zhì)細(xì)胞肥大

結(jié)構(gòu)蛋白是形成細(xì)胞骨架結(jié)構(gòu)的一部分，決定細(xì)胞形態(tài)和死亡率。反應(yīng)性星形膠質(zhì)細(xì)胞中結(jié)構(gòu)蛋白的上調(diào)誘導(dǎo)星形膠質(zhì)細(xì)胞骨架的重組，導(dǎo)致這些細(xì)胞肥大[16]。脊髓損傷后，反應(yīng)性星形膠質(zhì)細(xì)胞GFAP的表達(dá)比正常的星形膠質(zhì)細(xì)胞上調(diào)，此外，波形蛋白和巢蛋白也表現(xiàn)出上調(diào)[17]。反應(yīng)性星形膠質(zhì)細(xì)胞增生的部分特征是免疫反應(yīng)性GFAP的上調(diào)和星形膠質(zhì)細(xì)胞肥大[18]。在敲除GFAP和波形蛋白表達(dá)的位點(diǎn)后，脊髓損傷小鼠未觀察到星形膠質(zhì)細(xì)胞的活化和膠質(zhì)瘢痕形成，這表明兩種結(jié)構(gòu)蛋白都能補(bǔ)償彼此的功能，脊髓損傷后神經(jīng)膠質(zhì)瘢痕的形成需要增加GFAP和波形蛋白的表達(dá)[19]。

2008年Herrmann等[20]提出信號(hào)傳導(dǎo)及轉(zhuǎn)錄激活因子3(signal transducers and activators of transcription 3,STAT3)信號(hào)傳導(dǎo)參與脊髓損傷后星形膠質(zhì)細(xì)胞結(jié)構(gòu)蛋白的調(diào)節(jié)。在刪除細(xì)胞因子和生長(zhǎng)因子信號(hào)轉(zhuǎn)導(dǎo)子STAT3的脊髓損傷小鼠中，與對(duì)照組相比，來(lái)自STAT3-/-的小鼠表現(xiàn)出GFAP上調(diào)減弱，星形膠質(zhì)細(xì)胞肥大受阻以及脊髓損傷后膠質(zhì)細(xì)胞瘢痕形成中斷。2013年Wanner等[21]提出脊髓損傷成熟膠質(zhì)瘢痕邊界主要由新增的星形膠質(zhì)細(xì)胞、圍繞炎癥細(xì)胞及纖維化的膠質(zhì)細(xì)胞和其他細(xì)胞構(gòu)成。從脊髓損傷星形膠質(zhì)細(xì)胞中選擇性刪除STAT3，結(jié)果顯示星形膠質(zhì)細(xì)胞進(jìn)入瘢痕邊界及膠質(zhì)細(xì)胞圍繞炎癥細(xì)胞的過(guò)程失敗，并且出現(xiàn)這些細(xì)胞的擴(kuò)散和神經(jīng)元的損失。

2.2 星形膠質(zhì)細(xì)胞的增殖

靜息狀態(tài)下，成年大腦中的星形膠質(zhì)細(xì)胞處于不增殖的狀態(tài)。嚴(yán)重脊髓損傷后，靜止?fàn)顟B(tài)下的星形膠質(zhì)細(xì)胞重新進(jìn)入細(xì)胞周期[6]。星形膠質(zhì)細(xì)胞的增殖是促成膠質(zhì)瘢痕形成的一個(gè)重要方面，但星形膠質(zhì)細(xì)胞增殖有關(guān)的信號(hào)傳導(dǎo)依然沒(méi)有明確的闡述。

2014年Hong等[22]通過(guò)刪除Dicer1基因編碼成熟miRNA產(chǎn)生所需的酶，來(lái)觀察Dicer1缺乏的反應(yīng)性星形膠質(zhì)細(xì)胞在脊髓損傷后小鼠中增殖，結(jié)果顯示Dicer缺乏的星形膠質(zhì)細(xì)胞增殖被阻斷。通過(guò)對(duì)miR-17-5p在體外對(duì)反應(yīng)性星形膠質(zhì)細(xì)胞增殖作用的觀察，指出miR-17-5p模擬物能夠挽救Dicer缺乏星形膠質(zhì)細(xì)胞的增殖缺陷，并且通過(guò)JAK/STAT3途徑由白血病抑制因子(leukemiainhitory factor,LIF)啟動(dòng)反應(yīng)性星形膠質(zhì)細(xì)胞增殖。

膜聯(lián)蛋白A2(annexin A2,ANXA2)是Ca2+依賴(lài)性結(jié)合磷脂的蛋白，參與CNS的發(fā)育。2017年Chen等[23]發(fā)現(xiàn)在脊髓損傷后的大鼠ANXA2表達(dá)顯著上調(diào)，并且呈現(xiàn)動(dòng)態(tài)變化。雙重免疫熒光染色顯示，用于評(píng)估細(xì)胞增殖的增殖細(xì)胞核抗原(proliferating cell nuclear antigen,PCNA)出現(xiàn)在許多表達(dá)ANXA2的細(xì)胞中；敲低脊髓損傷后星形膠質(zhì)細(xì)胞ANXA2表達(dá)，導(dǎo)致脂多糖(lipopolysaccharide,LPS)刺激后PCNA表達(dá)增加，表明ANXA2在炎癥后抑制星形膠質(zhì)細(xì)胞增殖。

2.3 星形膠質(zhì)細(xì)胞的遷移

在內(nèi)皮素(endothelin,ET)、凝血酶和轉(zhuǎn)化生長(zhǎng)因子-β1(transforming growth factor-β1,TGF-β1)等因子的刺激下，反應(yīng)性星形膠質(zhì)細(xì)胞發(fā)生遷移，導(dǎo)致它們?cè)谑軗p部位累積，從而形成膠質(zhì)瘢痕[24-25]。

轉(zhuǎn)錄因子CCAAT增強(qiáng)子結(jié)合蛋白δ(human CCAAT/enhancer binding protein deta,C/EΒPδ)是對(duì)炎性因子有反應(yīng)的基因調(diào)節(jié)蛋白。2016年Wang等[26]實(shí)驗(yàn)發(fā)現(xiàn)，與C/EΒPδ正常小鼠相比，C/EΒPδ缺陷小鼠在脊髓損傷后28 d顯示膠質(zhì)瘢痕形成減少，并且在體外白細(xì)胞介素(intertleukin,IL)-1β刺激后，反應(yīng)性星形膠質(zhì)細(xì)胞中C/EΒPδ的表達(dá)增加且抑制小G蛋白(ras homolog gene family,member A,RhoA)的表達(dá)，隨后抑制星形膠質(zhì)細(xì)胞遷移。

Ski是一種進(jìn)化保守的蛋白質(zhì)，廣泛分布于各種組織和物種中的多功能轉(zhuǎn)錄調(diào)節(jié)因子。2017年Zhou等[27]首次發(fā)現(xiàn)Ski在脊髓損傷后的小鼠反應(yīng)性星形膠質(zhì)細(xì)胞中表達(dá)顯著上調(diào)。2017年Zhao等[28-29]又發(fā)現(xiàn)，在脊髓損傷小鼠中，當(dāng)Ski被小干擾RNA(siRNA)敲低時(shí)，LPS誘導(dǎo)的星形膠質(zhì)細(xì)胞的遷移減弱，這表明Ski在星形膠質(zhì)細(xì)胞遷移中發(fā)揮重要作用。同時(shí)，當(dāng)Ski被完全沉默時(shí)，GFAP的表達(dá)水平下降。Ski對(duì)星形膠質(zhì)細(xì)胞遷移的調(diào)控作用可能是通過(guò)間接或直接抑制GFAP。

2.4 膠質(zhì)瘢痕的形成

脊髓損傷后約14 d左右，大量增生的星形膠質(zhì)細(xì)胞定向遷移到脊髓損傷區(qū)，與侵入病變區(qū)的成纖維細(xì)胞相互交織，形成膠質(zhì)瘢痕。腫瘤壞死因子-α刺激基因6(tumor necrosisfactor alpha stimulated gene-6,TSG-6)能夠響應(yīng)炎性細(xì)胞因子刺激迅速上調(diào)，保護(hù)組織免受炎癥的破壞。2016年Coulson-Thomas等[30]實(shí)驗(yàn)發(fā)現(xiàn)，TSG-6僅在成熟大鼠的大腦和脊髓中由GFAP+和CD44+的星形膠質(zhì)細(xì)胞表達(dá)。在脊髓損傷的大鼠中TSG-6表達(dá)急劇上調(diào)，并且TSG-6蛋白存在于膠質(zhì)瘢痕內(nèi)，表明TSG-6參與膠質(zhì)瘢痕的形成并賦予抗炎特性。Chen等[31]指出，CAP-Gly結(jié)構(gòu)域的細(xì)胞質(zhì)連接蛋白3(CAP-Gly domain containing linker protein 3,CLIP3)在脊髓損傷第3天表達(dá)達(dá)到峰值，CLIP3和STAT3染色陽(yáng)性細(xì)胞數(shù)量之間存在相關(guān)性，證實(shí)CLIP3在脊髓損傷后與STAT3相互作用，共同參與膠質(zhì)瘢痕的形成。

3 膠質(zhì)瘢痕對(duì)神經(jīng)元軸突的影響

脊髓損傷后，反應(yīng)性星形膠質(zhì)細(xì)胞增生，形成膠質(zhì)瘢痕，參與炎癥、免疫反應(yīng)以及對(duì)神經(jīng)元軸突再生產(chǎn)生影響。在CNS損傷后，受損軸突不能再生的主要原因是膠質(zhì)瘢痕中反應(yīng)性星形膠質(zhì)細(xì)胞分泌的硫酸軟骨素和硫酸角質(zhì)素蛋白聚糖的沉積，對(duì)神經(jīng)元再生產(chǎn)生抑制作用[32-33]。2016年Anderson等[7]提出，膠質(zhì)瘢痕的形成不是造成嚴(yán)重?fù)p傷后成熟CNS軸突再生的主要原因。星形膠質(zhì)細(xì)胞可以支持在發(fā)育期或成熟CNS損傷后神經(jīng)元軸突的生長(zhǎng)[34]。嚴(yán)重的CNS損傷后，只有當(dāng)形成瘢痕的星形膠質(zhì)橋出現(xiàn)時(shí)，成熟神經(jīng)元的軸突生長(zhǎng)程序基因才會(huì)激活，引起損傷CNS的軸突再生[35-36]。目前，大多數(shù)學(xué)者認(rèn)為，在CNS損傷后的急性期，膠質(zhì)瘢痕可以通過(guò)預(yù)防炎性細(xì)胞和各種炎性因子的擴(kuò)散，從而減輕損傷區(qū)組織炎性反應(yīng)及保護(hù)原來(lái)完好的組織免于繼發(fā)性損傷[14,37]；后期，由于膠質(zhì)瘢痕的形成，對(duì)神經(jīng)元軸突再生構(gòu)成障礙及釋放多種抑制性因子，如RhoA、硫酸軟骨素蛋白聚糖(chondroitin sulphate proteoglycan,CSPG)、人蛋白酪氨酸磷酸酶受體S(human protein tyrosine phosphatasereceptor type S,PTPRS)等[38-39]。

4 總結(jié)

嚴(yán)重脊髓損傷后運(yùn)動(dòng)及感覺(jué)功能的恢復(fù)依然是患者康復(fù)的重要指標(biāo)，但目前仍沒(méi)有完善、明確、有效的治療方案。近年來(lái)，對(duì)于脊髓損傷后影響神經(jīng)元再生的研究逐漸增多，但涉及的病理機(jī)制依然不夠明確。對(duì)嚴(yán)重脊髓損傷后膠質(zhì)瘢痕形成機(jī)制及作用的研究，可能為將來(lái)嚴(yán)重CNS損傷后神經(jīng)功能的恢復(fù)帶來(lái)希望。

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