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干細(xì)胞衍生的外泌體在肝臟疾病治療中的作用

2023-04-29 21:01:07王卓然朱冰余麗梅游紹莉
臨床肝膽病雜志 2023年3期
關(guān)鍵詞:外泌體干細(xì)胞

王卓然 朱冰 余麗梅 游紹莉

摘要:肝臟容易受多種病因影響發(fā)生肝損傷,嚴(yán)重情況下可引起其合成、解毒、代謝和生物轉(zhuǎn)化等功能發(fā)生障礙,當(dāng)前針對肝衰竭、失代償性肝硬化等終末期肝病仍缺乏高效的臨床治療手段。近年來間充質(zhì)干細(xì)胞的臨床療效已被證實(shí),基于干細(xì)胞外泌體的相關(guān)治療成為研究熱點(diǎn)。本文介紹了干細(xì)胞外泌體治療的優(yōu)勢、機(jī)制研究進(jìn)展、臨床前研究現(xiàn)狀等。從目前研究結(jié)果來看,干細(xì)胞衍生的外泌體治療肝臟疾病具有良好應(yīng)用前景,但臨床前研究仍需進(jìn)一步深入,臨床研究有待開展。

關(guān)鍵詞:肝疾??; 干細(xì)胞; 間質(zhì)干細(xì)胞; 外泌體

基金項(xiàng)目:首都特色重點(diǎn)課題(Z151100004015019); 國家科技重大專項(xiàng)項(xiàng)目(2017ZX10203201-004)

Role of stem cell-derived exosomes in treatment of liver diseases

WANG Zhuoran1,2, ZHU Bing2, YU Limei1,3,4, YOU Shaoli2. (1. Guizhou Provincial Key Laboratory of Cell Engineering, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China; 2. Division of Liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China; 3. Collaborative Innovation Center of Tissue Damage Repair and Regenerative Medicine, Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563001, China; 4. Zunyi Stem Cell and Regenerative Medicine Engineering Research Center, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China)

Corresponding author:YU Limei, ylm720@sina.com (ORCID:0000-0002-3377-1202); YOU Shaoli, youshaoli1972@163.com (ORCID:0000-0001-8689-8509)

Abstract:

The liver is easily affected by a variety of factors to induce liver damage, which can cause disorders in the synthesis, detoxification, metabolism, and biotransformation functions of the liver in severe cases, and at present, there is still a lack of efficient clinical treatment methods for end-stage liver diseases such as liver failure and decompensated liver cirrhosis. Recent studies have confirmed the clinical efficacy of stem cells, and treatment methods based on stem cell-derived exosomes have become a research hotspot. This article introduces the advantages of treatment based on stem cell-derived exosomes, the research advances in related mechanisms, and the current status of preclinical research. Current research findings suggest that treatment based on stem cell-derived exosomes has a good application prospect in the treatment of liver diseases, but it is still needed to conduct in-depth preclinical and clinical studies.

Key words:

Liver Diseases; Stem Cells; Mesenchymal Stem Cells; Exosomes

Research funding:

Capital Clinical Characteristic Application Research on Funded Projects (Z151100004015019); National Foundation for Science and Technology Development(2017ZX10203201-004)

肝臟雖然是人體內(nèi)少數(shù)具有強(qiáng)大再生能力的器官,但是當(dāng)肝功能嚴(yán)重受損發(fā)展成肝衰竭或失代償期肝硬化時(shí),肝細(xì)胞強(qiáng)大的自我再生能力會(huì)受到抑制,不能維持肝臟的正常功能。目前針對終末期肝病的治療尚缺乏特效藥物和手段,最有效的治療手段是肝移植,但是肝移植存在肝臟供體短缺、費(fèi)用昂貴、術(shù)后免疫排斥等諸多問題,尋找相應(yīng)的替代療法成為近年來肝臟疾病的研究熱點(diǎn)。

干細(xì)胞作為一類具有自我更新和多向分化潛能的細(xì)胞,近年來被廣泛應(yīng)用于組織的修復(fù)與再生。大量研究[1-4]證實(shí),干細(xì)胞移植可以有效促進(jìn)心、肺、肝、肌肉、骨骼等器官組織損傷的恢復(fù),對多種疾病起到良好的治療效果,因此干細(xì)胞移植作為肝移植的第一代替代療法已經(jīng)展開了深入的研究。干細(xì)胞治療的機(jī)制最初認(rèn)為是干細(xì)胞在損傷部位直接增殖分化,替代受損細(xì)胞以恢復(fù)組織功能[5]。隨著對細(xì)胞療法的深入研究發(fā)現(xiàn),干細(xì)胞通過旁分泌機(jī)制釋放的外泌體等多種生物活性物質(zhì),參與調(diào)節(jié)機(jī)體生物學(xué)功能,因而可能是更主要的治療機(jī)制[6],于是基于旁分泌機(jī)制的干細(xì)胞外泌體療法作為第二代肝移植替代技術(shù)得到了重視和發(fā)展,是在干細(xì)胞療法基礎(chǔ)上衍生而出的新興療法。

1 干細(xì)胞衍生外泌體治療機(jī)制研究進(jìn)展

1983年,研究者在網(wǎng)織紅細(xì)胞內(nèi)首次發(fā)現(xiàn)細(xì)胞外囊泡(extracellular vesicles,EV)[7],起初EV被認(rèn)為是細(xì)胞為了處理胞內(nèi)不需要的物質(zhì)而形成的“垃圾袋”,但是經(jīng)過多年的研究發(fā)現(xiàn),EV是幾乎所有類型細(xì)胞都會(huì)分泌的納米級囊泡微粒,其中包含蛋白質(zhì)、脂質(zhì)、核酸、細(xì)胞因子等生物活性物質(zhì),廣泛存在于機(jī)體的體液之中[8],EV也是細(xì)胞間通訊的重要載體,可以介導(dǎo)細(xì)胞間的信息交流,在人體正常生理活動(dòng)以及疾病的發(fā)生和進(jìn)展中發(fā)揮重要的作用[9]。國際細(xì)胞外囊泡協(xié)會(huì)將EV依據(jù)大小、生成機(jī)制等因素分為:外泌體、微囊泡以及凋亡小體三種類型[10],外泌體是其中發(fā)揮生物學(xué)功能最為強(qiáng)大且研究較為深入的一類。

外泌體經(jīng)細(xì)胞釋放后通過胞吞、胞飲、受體介導(dǎo)等多種方式與靶細(xì)胞相結(jié)合,對靶細(xì)胞產(chǎn)生多種作用,其磷脂雙層膜結(jié)構(gòu),可將其中的內(nèi)容物穩(wěn)定傳遞并避免被降解。膜上含有特定蛋白標(biāo)志物,可通過識別靶細(xì)胞上特異受體并與之結(jié)合或直接與靶細(xì)胞膜融合等途徑[11],激活靶細(xì)胞內(nèi)信號通路、調(diào)節(jié)活性酶維持組織穩(wěn)態(tài)、影響靶細(xì)胞內(nèi)mRNA的轉(zhuǎn)錄以及蛋白質(zhì)的生成等,實(shí)現(xiàn)細(xì)胞間信息交流,從而參與機(jī)體免疫調(diào)節(jié)、刺激血管生成、抑制氧化應(yīng)激反應(yīng)、調(diào)節(jié)細(xì)胞增殖凋亡、誘導(dǎo)組織干細(xì)胞分化等[12],實(shí)現(xiàn)損傷修復(fù)。

已有研究[13-15]證明干細(xì)胞所分泌的外泌體可以發(fā)揮與親代細(xì)胞類似的治療效果。干細(xì)胞外泌體在治療肝臟疾病方面進(jìn)行了較為深入的研究,其治療機(jī)制主要包括以下方面(圖1):(1)調(diào)節(jié)肝臟免疫穩(wěn)態(tài)。干細(xì)胞通過抑制炎癥相關(guān)信號通路、抑制促炎細(xì)胞因子、分泌抗炎細(xì)胞因子等調(diào)節(jié)免疫細(xì)胞功能,控制免疫反應(yīng)狀態(tài)[16-21]。(2)調(diào)節(jié)細(xì)胞增殖與凋亡:促進(jìn)肝細(xì)胞再生、減少肝細(xì)胞凋亡,保護(hù)受損肝組織[22-23]。(3)改善氧化應(yīng)激:調(diào)節(jié)組織抗氧化蛋白的表達(dá),抑制活性氧的產(chǎn)生[24-26];(4)減輕肝纖維化進(jìn)展:抑制肝星狀細(xì)胞的活化和成纖維細(xì)胞的產(chǎn)生,抑制膠原蛋白的分泌,減少細(xì)胞外基質(zhì)的沉積[14,27]。但干細(xì)胞外泌體在疾病中發(fā)揮的治療作用機(jī)制十分復(fù)雜,目前研究仍未能完全明確闡述,仍需要研究者不斷地探索研究。

2 不同來源干細(xì)胞衍生的外泌體發(fā)揮的生物學(xué)功能可能不同

不同組織來源的干細(xì)胞具有相似的細(xì)胞表型,但外泌體受親代細(xì)胞的來源、培養(yǎng)條件等諸多因素的影響,其中所含的蛋白質(zhì)、核酸以及細(xì)胞因子等活性物質(zhì)會(huì)產(chǎn)生不同程度的表達(dá)差異[28],因此,不同來源的干細(xì)胞產(chǎn)生的外泌體對受體細(xì)胞的作用也不盡相同[6,29]。

已有研究針對不同干細(xì)胞來源的外泌體進(jìn)行了差異蛋白的分析,Pires等[30]基于富含外泌體的間充質(zhì)干細(xì)胞(mesenchymal stem cells,MSC)培養(yǎng)基,分析其中的差異蛋白發(fā)現(xiàn),骨髓間充質(zhì)干細(xì)胞來源外泌體(bone marrow MSC -derived exosomes,BMSC-Exo)可能有較好的抗凋亡和氧化應(yīng)激的能力,而脂肪間充質(zhì)干細(xì)胞來源外泌體(adipose tissue MSC-derived exosomes,AMSC-Exo)可能有抗神經(jīng)細(xì)胞興奮性毒性的能力。Wang等[31]的研究則認(rèn)為BMSC-Exo可能有著良好的再生能力,AMSC-Exo可能有更好的免疫調(diào)節(jié)作用,而臍帶間充質(zhì)干細(xì)胞來源外泌體(umbilical cord MSC-derived exosomes,ucMSC-Exo)可能具有更為突出的組織損傷修復(fù)能力。當(dāng)然,這些差異仍需要在臨床實(shí)際應(yīng)用中加以論證。

不同組織來源干細(xì)胞的外泌體應(yīng)用于肝臟疾病治療的動(dòng)物實(shí)驗(yàn)研究在國內(nèi)外均有開展(表1)。

Zhao等[32]發(fā)現(xiàn)BMSC-Exo可以通過激活細(xì)胞自噬來減輕D-GalN/LPS誘導(dǎo)的肝細(xì)胞損傷和凋亡。Haga等[33]發(fā)現(xiàn)BMSC-Exo可調(diào)節(jié)巨噬細(xì)胞的募集和功能,抑制IL-1α、MIP-3β、干擾素γ誘導(dǎo)蛋白(interferon gamma-induced protein,IP)-10等促炎因子和趨化因子的表達(dá)水平,以提高D-GalN/TNFα誘導(dǎo)的肝衰竭小鼠的存活率。Rong等[34]證明,在對CCL4誘導(dǎo)的肝纖維化大鼠模型治療中,BMSC-Exo治療組的治療效果要優(yōu)于BMSC治療組,且BMSC-Exo治療可有效減輕模型大鼠的肝纖維化程度。在Lu等[35]的研究中顯示,BMSC-Exo可通過調(diào)節(jié)肝臟和巨噬細(xì)胞中miR-223-3p水平和STAT3的表達(dá),抑制自身免疫性肝炎小鼠肝臟中炎性細(xì)胞因子的釋放,減輕炎癥反應(yīng)。Liu等[36]實(shí)驗(yàn)證明AMSC-Exo中的miR-17抑制巨噬細(xì)胞內(nèi)炎性小體的激活,減輕炎癥反應(yīng),改善D-GalN/LPS誘導(dǎo)的ALF小鼠生存率。Watanabe等[15]證明了AMSC來源的細(xì)胞外囊泡(AMSC-EV)可以在NASH小鼠模型中改善受損肝功能,減少膠原聚積,減輕纖維化進(jìn)程,增加肝內(nèi)抗炎巨噬細(xì)胞的數(shù)量,維持NASH小鼠肝臟穩(wěn)態(tài)。Jin等[37]的研究發(fā)現(xiàn),經(jīng)AMSC-EV輸注治療可以改善ALF大鼠肝臟的炎癥水平,促進(jìn)肝細(xì)胞的增殖再生,抑制肝細(xì)胞的凋亡,改善ALF大鼠生存率。Wu等[38]證明在對乙酰氨基酚(APAP)誘導(dǎo)的肝細(xì)胞損傷模型和ALF小鼠模型中,ucMSC-Exo可以下調(diào)炎性細(xì)胞因子的分泌水平,激活PI3K/AKT和ERK1/2信號通路,減少氧化應(yīng)激,抑制細(xì)胞凋亡,發(fā)揮保肝作用。Yan等[24]發(fā)現(xiàn)ucMSC-Exo能夠改善CCl4導(dǎo)致的急性肝損傷小鼠模型受損的肝功能,調(diào)節(jié)ERK1/2磷酸化、抗凋亡蛋白Bcl-2的表達(dá)以及NF-κB、caspase3/9等信號通路,減少細(xì)胞的氧化應(yīng)激損傷和凋亡。Chen等[39]研究發(fā)現(xiàn)經(jīng)血來源間充質(zhì)干細(xì)胞外泌體中含有ICAM-1、血管生成素(angiopoietin)-2、Axl等多種細(xì)胞因子,尾靜脈注射經(jīng)血來源間充質(zhì)干細(xì)胞外泌體可以減少D-GalN/LPS誘導(dǎo)的ALF小鼠模型肝臟中單個(gè)核細(xì)胞以及凋亡活性蛋白caspase3的數(shù)量,改善小鼠肝功能,提高存活率。

以上這些研究中均未對不同組織來源的干細(xì)胞外泌體治療效果進(jìn)行深入對比研究,因此在肝臟疾病臨床實(shí)際治療中,哪種組織來源的干細(xì)胞外泌體療效更好,目前并未有明確研究結(jié)果。

3 不同的環(huán)境下干細(xì)胞衍生的外泌體可能不同

干細(xì)胞釋放的外泌體會(huì)受生長環(huán)境不同而產(chǎn)生差異,這一過程可能是干細(xì)胞與其周圍微環(huán)境共同調(diào)節(jié)的結(jié)果[9]。許多研究證明,改變干細(xì)胞的培養(yǎng)環(huán)境會(huì)影響生物活性物質(zhì)的分泌,例如對干細(xì)胞進(jìn)行低氧、缺血或者添加細(xì)胞因子(如IFNγ、TNFα和IL-6)等的預(yù)處理,可以改變干細(xì)胞外泌體中蛋白質(zhì)、mRNA、miRNA以及細(xì)胞因子等的組成和含量,這種異質(zhì)性可以影響外泌體發(fā)揮免疫調(diào)節(jié)、促進(jìn)再生、抗氧化等作用(表2)。

Zhang等[40]的研究證明,經(jīng)TNFα預(yù)處理的ucMSC-Exo(T-Exo)有更好的抗炎作用,在D-GalN/LPS誘導(dǎo)的ALF小鼠模型中,T-Exo治療改善了ALF小鼠肝臟的病理變化,抑制了NLRP3相關(guān)通路的表達(dá),改善了炎癥反應(yīng)。Shao等[19]發(fā)現(xiàn),經(jīng)過IL-6刺激處理的ucMSC-Exo中miR-455-3P表達(dá)水平更高,可以抑制巨噬細(xì)胞的活化、減少促炎細(xì)胞因子的表達(dá)、刺激肝細(xì)胞增殖并改善CCl4誘導(dǎo)的急性炎癥性肝損傷小鼠的組織損傷情況。Takeuchi等[16]證明經(jīng)過IFNγ預(yù)處理的AMSC細(xì)胞外囊泡對CCl4誘導(dǎo)的肝硬化小鼠的治療起到抗炎和抗纖維化的作用,IFNγ預(yù)處理的AMSC細(xì)胞外囊泡中含有多種抗炎巨噬細(xì)胞誘導(dǎo)蛋白,可以促進(jìn)M2型巨噬細(xì)胞和Treg細(xì)胞的產(chǎn)生,提高細(xì)胞的活性與吞噬能力,促進(jìn)小鼠受損肝臟組織的修復(fù)。Temnov等[25]的研究認(rèn)為低氧環(huán)境培養(yǎng)MSC可以改善中多種蛋白質(zhì)如硫氧還蛋白、半乳糖凝集素-1以及超氧化物歧化酶的表達(dá)水平升高,低氧環(huán)境培養(yǎng)MSC輸注治療APAP誘導(dǎo)的ALF小鼠,可以減輕其炎癥反應(yīng)和組織損傷情況、促進(jìn)肝再生。Chen等[41]研究發(fā)現(xiàn),BMSC與肝細(xì)胞共培養(yǎng)的培養(yǎng)基對D-GalN誘導(dǎo)的受損L02細(xì)胞以及ALF大鼠模型有良好的治療效果。在BMSC與肝細(xì)胞共培養(yǎng)的培養(yǎng)基中IL-6和IL-10等細(xì)胞因子的表達(dá)更高,可以提高受損細(xì)胞的細(xì)胞活力,改善ALF大鼠肝臟結(jié)構(gòu),提高ALF大鼠存活率。

已有研究[42-43]顯示外泌體中的特異性蛋白質(zhì)、miRNA含量可隨著機(jī)體疾病狀態(tài)而發(fā)生波動(dòng),因而有研究提出外泌體中存在的mRNA、miRNA和蛋白質(zhì)可作為疾病診斷、個(gè)性化治療和預(yù)后評估的重要標(biāo)志物。以上研究證實(shí),疾病狀態(tài)導(dǎo)致機(jī)體內(nèi)環(huán)境的改變也會(huì)影響干細(xì)胞外泌體分泌的活性物質(zhì)的表達(dá),進(jìn)而影響干細(xì)胞外泌體治療的療效。

4 臨床及臨床前研究現(xiàn)狀

隨著對細(xì)胞移植研究的深入,細(xì)胞療法的不足也逐漸顯現(xiàn):靜脈注射干細(xì)胞易在肺部毛細(xì)血管滯留,可能堵塞血管,難以大量歸巢[44];干細(xì)胞在體內(nèi)存活期較短易被清除[45];干細(xì)胞難以產(chǎn)生具有穩(wěn)定表型的細(xì)胞,存在致瘤風(fēng)險(xiǎn)等[46]。干細(xì)胞外泌體應(yīng)用于臨床治療在理論上具有更大的優(yōu)勢:外泌體體積小易達(dá)患處、免疫原性更低、便于保存運(yùn)輸、致瘤風(fēng)險(xiǎn)較低、不易發(fā)生外源性感染等[47-49]。目前干細(xì)胞外泌體在部分疾病的治療上表現(xiàn)出高效穩(wěn)定的治療效果,并且有研究[50]證明外泌體可被肝巨噬細(xì)胞內(nèi)化,有更好的肝臟靶向性。因此,干細(xì)胞外泌體可能在肝病的治療上更具優(yōu)勢。

關(guān)于干細(xì)胞外泌體在肝臟疾病治療中的研究,動(dòng)物實(shí)驗(yàn)研究較為豐富(表1),研究結(jié)論基本一致,均證實(shí)了干細(xì)胞外泌體可發(fā)揮抑制肝臟炎癥、促進(jìn)肝再生、提高生存率等作用。從https://clinicaltrials.gov/上了解已注冊的有關(guān)干細(xì)胞外泌體的臨床治療性研究主要聚焦于呼吸系統(tǒng)、運(yùn)動(dòng)系統(tǒng)和循環(huán)系統(tǒng)等疾病的治療觀察(圖2),其中有23項(xiàng)應(yīng)用于呼吸系統(tǒng)疾病,6項(xiàng)應(yīng)用于運(yùn)動(dòng)系統(tǒng)疾病,循環(huán)系統(tǒng)疾病、皮膚疾病及腫瘤各有5項(xiàng),其他疾病27項(xiàng),但尚未看到關(guān)于無細(xì)胞療法治療肝病的臨床研究報(bào)道。

在實(shí)際臨床治療研究中,目前干細(xì)胞外泌體治療理論分析仍有不足:缺乏靈敏、高效、低成本的外泌體提取鑒定標(biāo)準(zhǔn)化方法;因細(xì)胞異質(zhì)性難以鑒定外泌體數(shù)量和質(zhì)量;外泌體發(fā)揮治療作用的具體因子仍需進(jìn)一步深入確認(rèn);適合的治療劑量和最佳給藥途徑等問題仍需深入驗(yàn)證,這些都是干細(xì)胞外泌體治療難以開展臨床治療性研究的瓶頸問題。

5 展望

綜上所述,應(yīng)用干細(xì)胞外泌體開展的試驗(yàn)研究近年不斷涌現(xiàn),并已取得一定的進(jìn)展,但在臨床治療性研究中尚未廣泛開展,離臨床實(shí)際應(yīng)用還有一定的距離。在實(shí)際臨床治療上選用什么組織來源干細(xì)胞衍生的外泌體、如何統(tǒng)一干細(xì)胞的樣的培養(yǎng)條件、如何標(biāo)準(zhǔn)化外泌體的提取與鑒定及在什么疾病狀態(tài)下開展治療最為有效都是干細(xì)胞外泌體應(yīng)用于臨床試驗(yàn)研究中亟待解決的問題。同時(shí),針對干細(xì)胞外泌體的基礎(chǔ)研究仍需進(jìn)一步深入,干細(xì)胞外泌體在安全性、異質(zhì)性、作用機(jī)制等方面的細(xì)節(jié)仍有較大探索和完善的空間。

總之,干細(xì)胞外泌體在肝臟疾病的治療中具有較大的潛力,隨著干細(xì)胞及其外泌體相關(guān)研究的不斷深入,上述這些問題在研究中一定會(huì)逐步解決,干細(xì)胞外泌體將展現(xiàn)出良好的治療前景。

利益沖突聲明:所有作者均聲明不存在利益沖突。

作者貢獻(xiàn)聲明:游紹莉、王卓然負(fù)責(zé)論文起草與撰寫;游紹莉、朱冰負(fù)責(zé)擬定寫作思路,指導(dǎo)撰寫文章并最后定稿。

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收稿日期:

2022-07-30;錄用日期:2022-09-21

本文編輯:林姣

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