肝卵圓細(xì)胞的起源、標(biāo)志物、調(diào)控和應(yīng)用前景

王正洋(綜述) 李曉波 殷蓮華(審校)

(復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院生理與病理生理學(xué)系 上海 200032)

肝卵圓細(xì)胞的起源、標(biāo)志物、調(diào)控和應(yīng)用前景

王正洋(綜述) 李曉波 殷蓮華△(審校)

(復(fù)旦大學(xué)基礎(chǔ)醫(yī)學(xué)院生理與病理生理學(xué)系 上海 200032)

肝臟在機(jī)體內(nèi)發(fā)揮著重要作用,包括糖和脂質(zhì)代謝,血漿蛋白的合成和對(duì)內(nèi)外源性毒物的解毒作用等。目前肝臟的慢性疾病是導(dǎo)致人類死亡的重要原因。肝臟依靠肝細(xì)胞的自我更新和肝卵圓細(xì)胞的增殖分化兩大途徑參與肝損傷的修復(fù)。然而,我們對(duì)肝卵圓細(xì)胞的起源、特異性標(biāo)志物、信號(hào)通路的調(diào)控等方面依然尚未完全闡明。最近一些研究通過運(yùn)用新的分離技術(shù)和基因系譜追蹤技術(shù)對(duì)肝卵圓細(xì)胞的起源和生物學(xué)功能有新的發(fā)現(xiàn)。本文較詳盡地對(duì)以上內(nèi)容進(jìn)行了綜述。

肝卵圓細(xì)胞; 肝損傷; 標(biāo)志物; 信號(hào)通路

哺乳動(dòng)物的肝組織具有強(qiáng)大的損傷后再生能力,主要通過兩大途徑:其一通過肝細(xì)胞的增殖進(jìn)行肝再生,如急性肝損傷和正常肝臟的部分切除[1];其二當(dāng)肝細(xì)胞增殖受到抑制時(shí),通過膽管反應(yīng)(ductular reactions)及其伴隨的肝卵圓細(xì)胞(oval cells)增殖和分化進(jìn)行肝再生,如慢性肝損傷和肝腫瘤[2]。肝卵圓細(xì)胞又被稱為反應(yīng)性膽管細(xì)胞(reactive ductal cells),是一種具有卵圓形的細(xì)胞核、直徑大約10 μm、高核質(zhì)比增殖能力很強(qiáng)的肝前體細(xì)胞[3],可分化為肝膽管上皮細(xì)胞和肝細(xì)胞,因此被普遍認(rèn)為是肝臟的干細(xì)胞[4]。肝卵圓細(xì)胞激活且大量增殖后可向肝實(shí)質(zhì)內(nèi)遷移,破壞正常肝組織結(jié)構(gòu),甚至可導(dǎo)致肝硬化的發(fā)生[5]。其遷移、動(dòng)員和歸巢受到多種信號(hào)分子的調(diào)控,包括多種細(xì)胞黏附分子、細(xì)胞因子和趨化性分子[6]。深入研究肝卵圓細(xì)胞的來源、標(biāo)志物和調(diào)控其增殖與分化的信號(hào)通路對(duì)肝卵圓細(xì)胞的臨床應(yīng)用非常重要。然而目前學(xué)術(shù)界對(duì)肝卵圓細(xì)胞的上述生物學(xué)特性仍然尚未完全闡明,這嚴(yán)重制約了肝卵圓細(xì)胞的應(yīng)用前景。本文對(duì)肝卵圓細(xì)胞的起源、標(biāo)志物、調(diào)控和應(yīng)用前景進(jìn)行綜述,有助于該細(xì)胞的理論研究和未來的臨床應(yīng)用。

肝卵圓細(xì)胞來源 雖然目前對(duì)肝卵圓細(xì)胞的存在已經(jīng)形成共識(shí),但對(duì)其起源尚存在爭議,以下3種來源方式得到較為廣泛的研究。

來源于骨髓 1999年P(guān)etersen等[7]將雄性小鼠的骨髓移植到雌性小鼠體內(nèi)后,雌性小鼠肝臟中約有0.14%的肝細(xì)胞帶有Y染色體。此外,該研究人員還通過免疫磁珠分選中毒性肝損傷過程中大量增殖的肝卵圓細(xì)胞,不僅表達(dá)肝組織表面標(biāo)志物如A6、AFP,也可以表達(dá)造血系統(tǒng)相關(guān)抗原,如CD34、CD45、Sca-1和Thy-1[8]。2007年P(guān)iscaglia等[9]的研究證實(shí),粒細(xì)胞集落刺激因子(granulocyte-colony stimulating factor,G-CSF)可以通過促進(jìn)骨髓來源的前體細(xì)胞遷移至肝臟從而參與肝組織的修復(fù)過程,并且G-CSF能夠促進(jìn)肝卵圓細(xì)胞的激活和增殖。以上研究結(jié)果提示,肝卵圓細(xì)胞可能來源于骨髓。然而,Wang等[10]發(fā)現(xiàn)骨髓來源的細(xì)胞主要是通過細(xì)胞融合過程參與肝修復(fù)過程,而非分化為肝卵圓細(xì)胞。Rountree等[11]將綠色熒光蛋白(green fluorescent protein,GFP)標(biāo)記的骨髓細(xì)胞移植入免疫缺陷的小鼠體內(nèi),通過免疫熒光、細(xì)胞流式和qRT-PCR實(shí)驗(yàn)發(fā)現(xiàn)在中毒性肝損傷過程中,骨髓來源的細(xì)胞可遷移至肝臟,但并未分化為肝細(xì)胞、膽管細(xì)胞和肝卵圓細(xì)胞,也并未表達(dá)肝組織相關(guān)的抗原?？梢?雖然骨髓來源的細(xì)胞在肝損傷的修復(fù)過程中發(fā)揮重要作用,但并未通過未分化為肝卵圓細(xì)胞發(fā)揮作用。

來源于肝星狀細(xì)胞 肝星狀細(xì)胞(hepatic stellate cells,HSCs)是一種可分泌細(xì)胞外基質(zhì)的肝臟細(xì)胞,具有重要的生物學(xué)功能。其靜息態(tài)時(shí)儲(chǔ)存有大量的類維生素A,存在于肝竇內(nèi)皮細(xì)胞(sinusoidal endothelial cells)和肝細(xì)胞之間的Disse間隙內(nèi),Disse間隙具有干細(xì)胞小體(stem cell niches)的特點(diǎn),激活后可分化為肌成纖維細(xì)胞,進(jìn)而導(dǎo)致肝纖維化的發(fā)生[12]。目前有研究發(fā)現(xiàn)它具有間充質(zhì)干細(xì)胞(mesenchymal stem cell,MSC)的特征,體外培養(yǎng)過程中某一時(shí)段其基因表達(dá)譜與肝卵圓細(xì)胞相似,可分化為成熟肝細(xì)胞[13]。利用Gfap(glial fibrillary acidic protein )和Acta2啟動(dòng)子構(gòu)建的原基分布圖(fate-mapping)實(shí)驗(yàn)顯示,激活后的肝星狀細(xì)胞可表達(dá)肝卵圓細(xì)胞相關(guān)抗原,而且可進(jìn)一步分化為肝細(xì)胞[14]。Kordes等[13]研究發(fā)現(xiàn),將肝星狀細(xì)胞移植到肝損傷的大鼠體內(nèi),可以分化為成熟的肝細(xì)胞和膽管上皮細(xì)胞,進(jìn)一步研究發(fā)現(xiàn)肝星狀細(xì)胞通過間質(zhì)上皮轉(zhuǎn)化(mesenchymal-to-epithelial transition,MET)過程分化為上皮細(xì)胞黏附分子(epithelial cell adhesion molecule,EpCAM)陽性細(xì)胞,后者是肝卵圓細(xì)胞和膽管細(xì)胞的常見表面標(biāo)志物。Tatematsu等[15]在2-乙酰氨基芴/大部肝切除模型中(常用的抑制肝細(xì)胞增殖,且可以促進(jìn)肝卵圓細(xì)胞增殖的肝損傷模型),將雄性小鼠來源的GFP+的肝星狀細(xì)胞移植到雌性小鼠體內(nèi),結(jié)果顯示肝星狀細(xì)胞可以分化為肝細(xì)胞和膽管細(xì)胞。以上結(jié)果說明肝星狀細(xì)胞可能是肝卵圓細(xì)胞的來源。然而,Lua等[16]利用卵磷脂視黃醇酰基轉(zhuǎn)移酶(lecithin retinol acyltransferase,LRAT)和MESP1(mesoderm posterior 1 homolog)家系追蹤實(shí)驗(yàn)(lineage-tracing experiments)發(fā)現(xiàn)在肝損傷的小鼠肝組織中,肝星狀細(xì)胞并不能分化為上皮細(xì)胞。因此,關(guān)于肝卵圓細(xì)胞是否來源于星狀細(xì)胞,仍有待進(jìn)一步闡明。

來源于膽管上皮細(xì)胞 Hering小管連接膽小管和膽管,由肝細(xì)胞和膽管細(xì)胞構(gòu)成,正常肝臟Hering小管周圍可發(fā)現(xiàn)少數(shù)孤立的小立方形細(xì)胞,肝損傷后其周圍可發(fā)生膽管反應(yīng),并伴隨肝卵圓細(xì)胞的增殖[17]。Furuyama等[18]利用Sry(sex determining region Y)-box9(Sox9)品系追蹤模型,發(fā)現(xiàn)具有干細(xì)胞性質(zhì)的Sox9陽性細(xì)胞在肝臟往往聚集于膽道周圍,推測Hering小管可能是肝卵圓細(xì)胞的重要的起源位置。Rodrigo-Torres等[19]利用三苯氧胺(tamoxifen)誘導(dǎo)的Hnf1βCreER/R26RYfp/LacZ小鼠追蹤Hnf1β+膽管細(xì)胞,結(jié)果顯示肝卵圓細(xì)胞來源于Hnf1β+膽管細(xì)胞。在正常的肝組織中,Hnf1β+膽管細(xì)胞并不能分化為肝細(xì)胞,但在某些肝損傷過程中,Hnf1β+膽管細(xì)胞可以分化為肝細(xì)胞。Foxl1 (Forkhead box L1),Trop2(encoded by tumor-associated calcium signal transducer 2)和Lgr5(leucine-rich-repeat-containing G-protein-coupled receptor 5)是最近被發(fā)現(xiàn)的能相對(duì)特異性地表達(dá)于肝卵圓細(xì)胞表面的標(biāo)志物,而且Foxl1+和Trop2+細(xì)胞也表達(dá)EpCAM和CK19(keratin 19)蛋白,培養(yǎng)膽管細(xì)胞過程中可以表達(dá)Lgr5蛋白[20],這些結(jié)果說明至少有一部分的肝卵圓細(xì)胞來源于膽管細(xì)胞。

肝卵圓細(xì)胞的標(biāo)志物 明確肝卵圓細(xì)胞的標(biāo)志物對(duì)其功能研究和臨床應(yīng)用具有重要意義。然而,在肝疾病過程中,肝卵圓細(xì)胞往往處于動(dòng)態(tài)的不同分化階段,包括未分化的前體狀態(tài)、增殖狀態(tài)和分化終末狀態(tài)[21]。這些參與典型膽管反應(yīng)的肝卵圓細(xì)胞呈現(xiàn)顯著的異質(zhì)性,要精確區(qū)分這些細(xì)胞群體非常困難,這極大地阻礙了高特異性肝卵圓細(xì)胞標(biāo)志物的尋找。目前的研究認(rèn)為肝卵圓細(xì)胞可表達(dá):(1) 膽管上皮細(xì)胞標(biāo)志物,CK-7、CK-8、CK18、CK19、OV-6、GST π、connexin43和A6;(2)幼稚肝細(xì)胞標(biāo)志物,AFP、GGT、PKM2;(3) 造血干細(xì)胞標(biāo)志物,Thy-1、c-kit、CD34、Sca-1[21-24];(4) 神經(jīng)上皮細(xì)胞標(biāo)志物,嗜鉻粒蛋白A、神經(jīng)細(xì)胞黏附分子(neural cell adhesion molecule,N-CAM)、甲狀旁腺素相關(guān)蛋白[25]。一些相對(duì)特異的抗體,如OV6、A6和EpCAM已經(jīng)被廣泛用于確定分離肝卵圓細(xì)胞[26- 27]。肝卵圓細(xì)胞標(biāo)志物有如下特點(diǎn):(1)不僅表達(dá)于肝卵圓細(xì)胞,也可表達(dá)其他多種細(xì)胞類型;(2)幾乎沒有一種表面標(biāo)志物可以用來高度特異性地分離肝卵圓細(xì)胞;(3)肝卵圓細(xì)胞處于動(dòng)態(tài)過程中,常常處于不同的細(xì)胞形態(tài)且表達(dá)不同的表面標(biāo)志物,因此高純度地分離它們有很大困難;(4)肝卵圓細(xì)胞的基因組具有物種多態(tài)性,不同物種之間差異較大[28]。雖然存在以上諸多困難,但尋找表達(dá)相對(duì)恒定且特異的肝卵圓細(xì)胞標(biāo)志物仍然具有其必要性,值得進(jìn)一步深入研究,這會(huì)成為開啟肝卵圓細(xì)胞為臨床更好服務(wù)大門的鑰匙。

肝卵圓細(xì)胞增殖與分化的信號(hào)通路調(diào)控 研究調(diào)控肝卵圓細(xì)胞的激活、增殖與分化是更好地理解肝卵圓細(xì)胞介導(dǎo)的肝損傷修復(fù)與再生醫(yī)學(xué)的重要前提。目前認(rèn)為,調(diào)控肝卵圓細(xì)胞的增殖和分化是多種信號(hào)分子共同參與的生物學(xué)過程。越來越多的證據(jù)表明,多種細(xì)胞因子和信號(hào)通路參與肝卵圓細(xì)胞的激活、增殖和分化。Yeol等[29]通過gp130Y757F小鼠和 Socs3-/ΔAlb小鼠研究發(fā)現(xiàn),活化STAT3信號(hào)分子或者SOCS3基因的缺失可促進(jìn)肝卵圓細(xì)胞的增殖,而高表達(dá)SOCS3則可以抑制肝卵圓細(xì)胞的增殖。Sánchez等[30]除了證實(shí)激活的STAT3基因主要作用在肝卵圓細(xì)胞的增殖階段,還進(jìn)一步揭示了在肝卵圓細(xì)胞的不同發(fā)育階段信號(hào)分子對(duì)肝卵圓細(xì)胞的激活作用不同,如NF-κB的作用貫穿于肝卵圓細(xì)胞整個(gè)增殖分化階段。Martínez-Palacián等[31]通過重組基因和化學(xué)信號(hào)追蹤技術(shù)發(fā)現(xiàn)c-Met和表皮生長因子(epidermal growth factor receptor,EGFR)介導(dǎo)的信號(hào)通路可促進(jìn)肝卵圓細(xì)胞的增殖和存活。Yang等[32]研究發(fā)現(xiàn):(1) β-catenin及其靶基因高表達(dá)于增殖狀態(tài)的肝卵圓細(xì)胞中;(2)在肝卵圓細(xì)胞增殖的過程中Wnt/β-catenin通路持續(xù)激活;(3)Wnt/β-catenin通路可以促進(jìn)移植后的肝卵圓細(xì)胞克隆樣生長。以上結(jié)果表明Wnt/β-catenin通路在肝卵圓細(xì)胞的激活和增殖過程中發(fā)揮重要作用。其他一些重要的生長因子,如白介素-6 (interleukin-6,IL-6)、轉(zhuǎn)化生長因子(transforming growth factor,TGF)、白血病抑制因子(leukemia inhibitory factor,LIF)、干擾素-γ (interferon-γ,IFN-γ)、抑瘤素M (oncostatin M,OSM)、肝細(xì)胞生長因子(hepatocyte growth factor,HGF)和酸性成纖維細(xì)胞生長因子(acidic fibroblast growth factor,aFGF)等均參與了肝卵圓細(xì)胞的增殖分化過程[30-33]。

肝卵圓細(xì)胞的臨床應(yīng)用 目前對(duì)于終末期的肝疾病,肝移植是唯一行之有效的方法。但肝移植伴隨著許多副作用,如慢性腎功能衰竭[34]、移植后淋巴增生失調(diào)癥[35]和心血管并發(fā)癥[36]等。與肝移植相比,肝卵圓細(xì)胞移植具有如下優(yōu)勢:(1)直接來源于患者,無免疫排斥;(2)取少量的肝卵圓細(xì)胞即可大量體外擴(kuò)增,對(duì)患者創(chuàng)傷小;(3)具有雙向分化潛能,可分化為成熟肝細(xì)胞;(4)細(xì)胞小,不易堵塞血管導(dǎo)致門靜脈高壓;(5)多種肝損傷均有肝卵圓細(xì)胞增殖,因此可以被用來治療多種肝疾病[37]。然而移植肝卵圓細(xì)胞的效率偏低、肝功能的恢復(fù)不佳、移植后導(dǎo)致鏈接紊亂(disruption of gap junctions)和缺血性肝損傷(ischemic liver injury)[38]以及肝卵圓細(xì)胞的致瘤性[39]依然限制肝卵圓細(xì)胞的臨床應(yīng)用。因此,雖然利用肝卵圓細(xì)胞來治療終末期肝疾病的前景光明且優(yōu)勢明顯,但是在應(yīng)用于臨床之前還有大量的理論和技術(shù)難題需要闡明和改進(jìn)。

結(jié)語 肝卵圓細(xì)胞的激活、增殖和分化與機(jī)體內(nèi)環(huán)境密切相關(guān),受到一系列信號(hào)分子的調(diào)控。但其起源、標(biāo)志物和調(diào)控還尚未完全闡明。只有通過更多更深入的研究,肝卵圓細(xì)胞這一令人興奮的細(xì)胞才能夠更好地應(yīng)用到臨床及治療終末期肝疾病。

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The origin,marker,regulation and therapeutic potential of hepatic oval cells

WANG Zheng-yang, LI Xiao-bo, YIN Lian-hua△

(DepartmentofPhysiologyandPathophysiology,SchoolofBasicMedicalSciences,FudanUniversity,Shanghai200032,China)

The liver plays an vital role in glucose and lipid metabolism,synthesis of plasma proteins,and detoxification of xenobiotics.Liver chronic disease is one of the leading causes of death in China.Liver mass can be restored by two mechanisms:division of hepatocytes and hepatic oval cells (HOCs) proliferation and differentiation.However,the origin,specific markers and signaling pathways of HOCs have not been fully elucidated.Recent researches in HOCs isolation methods and genetic lineage tracing have enabled investigators to study multiple aspects of HOCs origin and biology.We reviewed the previous researches in detail.

hepatic oval cell; liver injury; marker; signaling pathways

國家自然科學(xué)基金(81270497)

Q28,R446.1

B

10.3969/j.issn.1672-8467.2017.02.015

2016-03-08;編輯:張秀峰)

△Corresponding author E-mail:lhyin@shmu.edu.cn

*This work was supported by the National Natural Science Foundation of China (81270497).