陳佳琦， 陳慧敏

(1. 寧波大學(xué)醫(yī)學(xué)院， 浙江 寧波 315000; 2. 寧波市第二醫(yī)院， 浙江 寧波 315000)

間充質(zhì)干細(xì)胞移植治療帕金森病的作用機(jī)制研究進(jìn)展

陳佳琦1， 陳慧敏2

(1. 寧波大學(xué)醫(yī)學(xué)院， 浙江 寧波 315000; 2. 寧波市第二醫(yī)院， 浙江 寧波 315000)

帕金森病(Parkinson′s Disease, PD)的主要病理改變是黑質(zhì)多巴胺能神經(jīng)元進(jìn)行性變性致紋狀體多巴胺遞質(zhì)濃度顯著降低，從而出現(xiàn)運(yùn)動(dòng)障礙。目前，藥物和外科手術(shù)治療可一定程度改善早期PD的部分臨床癥狀，但并不能阻止或逆轉(zhuǎn)多巴胺能神經(jīng)元變性。近些年，間充質(zhì)干細(xì)胞(Mesenchymal Stem Cells, MSCs)移植作為治療PD的最前沿方法，其療效備受矚目。本文就MSCs移植促進(jìn)PD神經(jīng)功能恢復(fù)的可能作用機(jī)制作一綜述。

間充質(zhì)干細(xì)胞；帕金森?。蛔饔脵C(jī)制

早在1968年，F(xiàn)riedenstein等[1]發(fā)現(xiàn)骨髓中存在一群非造血的多潛能細(xì)胞，其具貼壁和呈成纖維樣細(xì)胞生長特性。隨后，大量研究證實(shí)該細(xì)胞是一群能自我更新、多譜系分化和分泌多種生物活性因子的成體干細(xì)胞而稱之為“間充質(zhì)干細(xì)胞(Mesenchymal Stem Cells, MSCs)”。MSCs來源較廣[2]，骨髓、脂肪組織、外周血、羊膜、絨毛膜、胎盤、羊水和臍血中均可分離得到，其中骨髓中含量最為豐富。MSCs具多分化潛能，即特定微環(huán)境下能誘導(dǎo)分化為中胚層源性細(xì)胞，如成骨細(xì)胞、軟骨細(xì)胞、脂肪細(xì)胞、肌細(xì)胞和肌腱細(xì)胞等；也可分化為神經(jīng)細(xì)胞(如多巴胺能神經(jīng)元)、平滑肌細(xì)胞和內(nèi)皮細(xì)胞等內(nèi)、外胚層源性細(xì)胞[3-4]。其多譜系分化潛能為細(xì)胞替代治療神經(jīng)系統(tǒng)疾病，尤其是帕金森病(Parkinson′s Disease, PD)提供了可行性依據(jù)；同時(shí)也因其具有分泌多種神經(jīng)營養(yǎng)因子保護(hù)和促進(jìn)受損多巴胺能神經(jīng)元再生及分泌多種細(xì)胞因子、趨化因子而形成局部免疫抑制微環(huán)境為同種異體MSCs移植治療PD成為可能[5]。大量動(dòng)物實(shí)驗(yàn)和前期臨床試驗(yàn)中也發(fā)現(xiàn)MSCs移植治療PD不僅能增加腦內(nèi)多巴胺遞質(zhì)分泌水平，有效恢復(fù)運(yùn)動(dòng)障礙，還能降低對左旋多巴藥物的依懶性，但是MSCs移植治療PD的許多潛在作用機(jī)制尚待研究證實(shí)，本文就目前較為認(rèn)同的3種作用機(jī)制，即MSCs可自我更新和定向分化為多巴胺能神經(jīng)元，分泌多種生物活性因子及調(diào)節(jié)細(xì)胞代謝以保護(hù)和修復(fù)受損多巴胺能神經(jīng)元的相關(guān)研究進(jìn)展作一綜述，以進(jìn)一步闡明其作用機(jī)制。

1 自我更新和定向分化為多巴胺能神經(jīng)元

MSCs是一類中胚層來源的多能成體干細(xì)胞，無論在體還是離體，均具強(qiáng)大的自我更新和分裂增殖能力，且能保持未分化狀態(tài)。在特定微環(huán)境誘導(dǎo)下，MSCs可跨胚層定向分化為多巴胺能神經(jīng)元。Paldino等[6]發(fā)現(xiàn)腺苷酸環(huán)化酶激活劑(Forskolin)能誘導(dǎo)MSCs分化為特異性表達(dá)酪氨酸羥化酶(TH)、多巴胺轉(zhuǎn)運(yùn)蛋白(DAT)及孤兒核受體相關(guān)因子-1(Nurr1)的多巴胺能神經(jīng)元，從而可替代變性或丟失的多巴胺能神經(jīng)元重塑神經(jīng)功能和傳導(dǎo)通路。Park等[7]將鼠單側(cè)紋狀體經(jīng)6-羥多巴胺(6-OHDA)毀損處理30 d后，PET檢查發(fā)現(xiàn)該側(cè)放射性核素(18F-FP-CIT)標(biāo)記的多巴胺類似物含量相比正常側(cè)已下降至32%，隨后移植MSCs源性神經(jīng)前體細(xì)胞(MSCs-NPs)至毀損側(cè)紋狀體內(nèi)，24周后發(fā)現(xiàn)18F-FP-CIT含量上升至58%，免疫組化法發(fā)現(xiàn)移植組的TH和DAT表達(dá)水平上調(diào)顯著，且行為學(xué)研究表明移植組旋轉(zhuǎn)運(yùn)動(dòng)明顯緩解，推測可能是由于移植的MSCs-NPs在紋狀體區(qū)分化為多巴胺能神經(jīng)元并分泌多巴胺遞質(zhì)，從而改善安非他命誘導(dǎo)的PD鼠旋轉(zhuǎn)行為。有報(bào)道稱[8]，移植已分化的MSCs，即移植特異性表達(dá)TH的多巴胺能神經(jīng)元對改善PD鼠旋轉(zhuǎn)運(yùn)動(dòng)的療效優(yōu)于移植未分化的MSCs。然而，MSCs誘導(dǎo)分化的多巴胺能神經(jīng)元是否真正能和宿主細(xì)胞建立相應(yīng)突觸聯(lián)系并整合至黑質(zhì)-紋狀體通路，從根本上替代變性或丟失的多巴胺能神經(jīng)元，仍需大量實(shí)驗(yàn)研究進(jìn)一步證實(shí)。

2 分泌多種生物活性因子

2.1 神經(jīng)營養(yǎng)、抗細(xì)胞凋亡及血管再生

目前，大量研究表明MSCs能分泌神經(jīng)營養(yǎng)因子、細(xì)胞因子等多種生物活性因子，創(chuàng)造一個(gè)適合神經(jīng)細(xì)胞生長的局部微環(huán)境，從而直接或間接促進(jìn)受損多巴胺能神經(jīng)元修復(fù)或再生。Yasuda等[9]認(rèn)為GDNF、BDNF、Neurturin(NTN)、NGF、MANF、CDNF和GM-CSF等活性分子能營養(yǎng)和保護(hù)受損多巴胺能神經(jīng)元，使其免受各種神經(jīng)毒素?fù)p害，因而一定程度阻止或延緩多巴胺能神經(jīng)元進(jìn)行性退變。Ren等[10]用重組GDNF基因的慢病毒轉(zhuǎn)染MSCs并移植入經(jīng)1-甲基-4-苯基-1, 2, 3, 6-四氫吡啶(MPTP)毀損處理的PD猴紋狀體內(nèi)，發(fā)現(xiàn)移植組紋狀體區(qū)GDNF分泌水平明顯高于未移植組，SPECT檢測放射性核素(99 mTc-TRODAT-1)標(biāo)記的DAT表達(dá)顯著增高，免疫組化分析顯示TH陽性細(xì)胞也明顯升高，因而認(rèn)為可能是MSCs通過調(diào)控GDNF分泌水平，以保護(hù)多巴胺能神經(jīng)元免遭MPTP神經(jīng)毒素?fù)p傷。據(jù)相關(guān)報(bào)道[11]，將轉(zhuǎn)染Lmx1α和NTN基因的MSCs移植到PD猴黑質(zhì)致密部，48 h后該區(qū)域NTN分泌水平明顯增高，21 d后TH、DAT、Nurr1和Pitx-3基因表達(dá)也顯著上調(diào)，6個(gè)月后帕金森病統(tǒng)一評分量表(UPDRS)顯示PD癥狀明顯好轉(zhuǎn)，推測可能是Lmx1α過表達(dá)促進(jìn)MSCs分化為多巴胺能神經(jīng)元，同時(shí)高含量的NTN對受損多巴胺能神經(jīng)元起營養(yǎng)、修復(fù)和功能重建功效。Somoza等[12]發(fā)現(xiàn)外源性EGF、bFGF可促進(jìn)移植的MSCs分泌BDNF，使MSCs向TH陽性神經(jīng)元分化，且BDNF可進(jìn)一步激活酪氨酸激酶受體B(TrkB)，以促進(jìn)內(nèi)源性細(xì)胞分泌更多BDNF，從而保護(hù)多巴胺能神經(jīng)元免受6-OHDA神經(jīng)毒素?fù)p傷。相關(guān)研究發(fā)現(xiàn)MSCs也能直接刺激內(nèi)源性細(xì)胞分泌神經(jīng)生長因子(如EGF、BDNF、NT-3)，延緩或逆轉(zhuǎn)多巴胺能神經(jīng)元變性，并可促進(jìn)丟失的多巴胺能神經(jīng)元再生[13]。Jin等[14]發(fā)現(xiàn)MSCs能分泌NGF、BDNF等神經(jīng)營養(yǎng)因子促進(jìn)內(nèi)源性神經(jīng)前體細(xì)胞(NPCs)分化為多巴胺能神經(jīng)元(TH基因表達(dá)上調(diào))，進(jìn)而增加多巴胺遞質(zhì)含量，阻止或延緩黑質(zhì)-紋狀體多巴胺能通路進(jìn)行性退變。Park等[15]也發(fā)現(xiàn)MSCs能激活內(nèi)源性NPCs增殖，并促進(jìn)NPCs分化為多巴胺能神經(jīng)元；同時(shí)MSCs也可促進(jìn)表皮生長因子受體(EGFR)表達(dá)上調(diào)，EGF分泌顯著增加，從而提高新生多巴胺能神經(jīng)元的存活及整合能力，營養(yǎng)和保護(hù)殘存的多巴胺能神經(jīng)元。此外，MSCs能激活宿主小膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞，這些活化的膠質(zhì)細(xì)胞也可分泌多種營養(yǎng)因子(如GDNF、NGF、NT-3)而保護(hù)多巴胺能神經(jīng)元免遭MPTP神經(jīng)毒素?fù)p害，進(jìn)而促進(jìn)受損的多巴胺能神經(jīng)元再生[16-17]。研究發(fā)現(xiàn)MSCs還能分泌細(xì)胞外基質(zhì)(ECM)，有助于細(xì)胞對抗氧自由基損傷，減少細(xì)胞凋亡，進(jìn)而營養(yǎng)和修復(fù)損傷的多巴胺能神經(jīng)元[18]。有研究表明，受損腦區(qū)移植MSCs，則可明顯增高局部Bcl-2、G-CSF、BDNF表達(dá)水平，促進(jìn)多巴胺能神經(jīng)元修復(fù)及功能重建；同時(shí)可上調(diào)絲氨酸/蘇氨酸蛋白激酶(Akt)活性，降低caspase-3活性，從而抑制神經(jīng)細(xì)胞凋亡[19]。Wang等[20]也發(fā)現(xiàn)MSCs之所以能修復(fù)變性的多巴胺能神經(jīng)元，與其移植后局部所分泌的SDF-1α起抗細(xì)胞凋亡效應(yīng)密切相關(guān)。此外，MSCs是受損部位新生微血管的主要組成細(xì)胞，因而有學(xué)者認(rèn)為MSCs保護(hù)和修復(fù)多巴胺能神經(jīng)元可能與其分泌多種促內(nèi)皮細(xì)胞增殖因子和血管生成因子(如VEGF、FGF-2、Ang-1/Ang-2、HGF、IGF-1、MCP-1、SDF-1、PLGF和CXCL7)所致的微血管再生效應(yīng)息息相關(guān)[13, 21]。

2.2 免疫調(diào)控和抗炎作用

MSCs能通過細(xì)胞與細(xì)胞之間接觸，誘導(dǎo)免疫耐受，低表達(dá)MHCⅠ，不表達(dá)MHCⅡ和其它共刺激分子(CD86、CD80、CD40/CD40L和FasL)，同時(shí)MSCs能分泌IL-6、IL-10、IDO、TGF-β、PGE-2、NO和HO-1等多種免疫活性分子，也能促進(jìn)Toll樣受體(TLR)表達(dá)，抑制T細(xì)胞、B細(xì)胞、NK細(xì)胞和抗原提呈細(xì)胞活性[22]，這種免疫耐受和免疫抑制效應(yīng)為同種異體MSCs移植治療PD成為可能。最新一項(xiàng)研究發(fā)現(xiàn)自噬系統(tǒng)紊亂所致的α-synuclein儲(chǔ)積與PD的發(fā)生發(fā)展密切相關(guān)，而移植的MSCs可促進(jìn)LC3-Ⅱ陽性的自噬溶酶體形成，減少α-synuclein表達(dá)，進(jìn)而提高多巴胺能神經(jīng)元存活比率和促進(jìn)其功能恢復(fù)[23]。此外，神經(jīng)炎癥和小膠質(zhì)細(xì)胞大量活化也可導(dǎo)致多巴胺能神經(jīng)元進(jìn)行性變性。Chao等[24]發(fā)現(xiàn)MPTP可破壞PD鼠血腦屏障(BBB)致甘露糖結(jié)合凝集素(MBL)滲透入腦，激活小膠質(zhì)細(xì)胞而產(chǎn)生炎癥應(yīng)答，損傷多巴胺能神經(jīng)元；進(jìn)一步研究發(fā)現(xiàn)MSCs可通過修復(fù)BBB，降低MBL滲透，從而抑制小膠質(zhì)細(xì)胞活化，同時(shí)MSCs能分泌TGF-β1，調(diào)控免疫炎癥反應(yīng)，進(jìn)而保護(hù)多巴胺能神經(jīng)元免遭炎癥因子損傷。Kim等[25]也發(fā)現(xiàn)MSCs移植可抑制脂多糖(LPS)誘導(dǎo)的小膠質(zhì)細(xì)胞活化，減少誘導(dǎo)型一氧化氮合酶(iNOS)表達(dá)和TNF-α分泌，這種抗炎效應(yīng)能有效保護(hù)因炎癥而受損的多巴胺能神經(jīng)元。

3 調(diào)節(jié)細(xì)胞代謝

MSCs調(diào)節(jié)細(xì)胞代謝而保護(hù)神經(jīng)細(xì)胞鮮有報(bào)道。一項(xiàng)最新研究發(fā)現(xiàn)MSCs可調(diào)控細(xì)胞ATP、NAD+/NADH比率，降低高濃度谷氨酸對線粒體膜損傷，從而調(diào)節(jié)細(xì)胞能量代謝，減少神經(jīng)細(xì)胞變性[26]。Fu等[27]將MSCs移植入經(jīng)6-OHDA毀損處理的PD鼠黑質(zhì)紋狀體內(nèi)，氫質(zhì)子磁共振波譜(1H-MRS)分析顯示紋狀體區(qū)N-乙酰天冬氨酸(NAA)/肌酐(Cr)比率相比未移植組則明顯增高；而膽堿(Cho)/肌酐(Cr)比率則顯著降低，行為學(xué)研究發(fā)現(xiàn)移植組PD鼠旋轉(zhuǎn)次數(shù)明顯減少，神經(jīng)功能恢復(fù)更為顯著。Zhao等[28]研究了MSCs移植對PD鼠多巴胺及其代謝物的影響，高效液相色譜法測定結(jié)果表明MSCs移植后的紋狀體內(nèi)多巴胺(DA)、高香草酸(HVA)、二羥苯乙酸(DOPAC)含量及DA/HVA、DA/DOPAC比率均有不同程度增高，推測MSCs可能通過降低多巴胺代謝速度，進(jìn)而減少多巴胺自身氧化，從而改善阿撲嗎啡(APO)誘導(dǎo)的PD鼠旋轉(zhuǎn)行為。由此可見，MSCs可通過調(diào)節(jié)神經(jīng)細(xì)胞代謝而對多巴胺能神經(jīng)元起保護(hù)作用。此外，MSCs可分泌大量小囊泡，這些小囊泡可轉(zhuǎn)運(yùn)蛋白質(zhì)、脂質(zhì)和RNAs至鄰近細(xì)胞，盡管相關(guān)機(jī)制尚不清楚，但MSCs所分泌的小囊泡對保護(hù)和修復(fù)受損神經(jīng)細(xì)胞意義重大[29]。

4 小結(jié)

綜上所述，目前MSCs移植治療PD較為認(rèn)可的作用機(jī)制主要有MSCs移植可定向分化替代變性或缺失的多巴胺能神經(jīng)元；也可分泌多種生物活性因子，起神經(jīng)營養(yǎng)、抗細(xì)胞凋亡、微血管再生、免疫調(diào)控和抗炎效應(yīng)；此外，還可調(diào)節(jié)細(xì)胞代謝保護(hù)多巴胺能神經(jīng)元。當(dāng)然，更多其它潛在的作用機(jī)制尚需大量動(dòng)物實(shí)驗(yàn)和前期臨床試驗(yàn)研究進(jìn)一步探索、證實(shí)?？傊?，MSCs移植治療PD的上述作用機(jī)制并非相互獨(dú)立，而是相互依賴，相互影響，共同營養(yǎng)、修復(fù)和促進(jìn)受損多巴胺能神經(jīng)元再生，進(jìn)而提高多巴胺遞質(zhì)分泌水平，從病理基礎(chǔ)上阻止或逆轉(zhuǎn)黑質(zhì)-紋狀體通路進(jìn)行性退變，改善運(yùn)動(dòng)障礙。

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Research progress on function mechanism of Mesenchymal stem cells transplantation for Parkinson′s disease

CHEN Jia-qi1, CHEN Hui-min2

(1. Medical School， Ningbo University, NingBo 315000; 2. Ningbo No.2 Hospital , NingBo 315000, China)

The main pathological changes of Parkinson′s disease(PD) are the progressive degeneration of dopaminergic neurons in the area of substantia nigra, which results in dopamine reduced sharply in the striatum, and develops movement disorders. At present, to a certain extent, drug and surgical treatment can partially improve the clinical symptoms of early PD, but cannot prevent or reverse dopaminergic neuron degeneration. In recent years, Mesenchymal stem cells (MSCs) transplantation, as a forefront of treatment method for PD, attracts tremendous attention because of its curative effect. This article reviewed the possible function mechanisms of MSCs transplantation promote the neural functional recovery of PD.

Mesenchymal stem cells; Parkinson′s disease; function mechanism

2014-04-03；

2014-04-14

浙江省醫(yī)學(xué)會(huì)臨床科研基金項(xiàng)目(編號：2013XYC-A73)

陳佳琦，碩士，主要從事干細(xì)胞研究工作；

陳慧敏，主任醫(yī)師，教授，碩士生導(dǎo)師，專業(yè)方向?yàn)樯窠?jīng)系統(tǒng)疑難病的診治研究，E-mail：qjc600@163.com。

R742.5

A

2095-1736(2015)01-0082-04

doi∶10.3969/j.issn.2095-1736.2015.01.082