羊膜間充質(zhì)干細(xì)胞的免疫調(diào)節(jié)功能研究進展

歐陽文 廖正權(quán) 夏增飛 高雅 郭燕舞 孫海濤

羊膜間充質(zhì)干細(xì)胞的免疫調(diào)節(jié)功能研究進展

歐陽文1,2廖正權(quán)1,2夏增飛1,2高雅3郭燕舞1,2孫海濤1,2

羊膜間充質(zhì)干細(xì)胞是一類來源于羊膜的干細(xì)胞。相比較其他來源的干細(xì)胞，羊膜間充質(zhì)干細(xì)胞具有低免疫原性和免疫抑制的特點，這使得羊膜間充質(zhì)干細(xì)胞的移植副作用相對較小。羊膜間充質(zhì)干細(xì)胞移植治療一些炎癥相關(guān)疾病，取得了較好的效果，相關(guān)的臨床試驗也逐步開展。現(xiàn)針對羊膜間充質(zhì)干細(xì)胞在免疫調(diào)節(jié)方面的機制雖然有一定的認(rèn)識，但仍不是很清楚。本文針對現(xiàn)階段關(guān)于羊膜間充質(zhì)干細(xì)胞的免疫調(diào)節(jié)功能進行討論，為進一步開展相關(guān)方面的研究奠定理論基礎(chǔ)。

羊膜間充質(zhì)干細(xì)胞； 免疫調(diào)節(jié)； 單核巨噬細(xì)胞； T淋巴細(xì)胞； 樹突細(xì)胞

羊膜間充質(zhì)干細(xì)胞來源于胚胎中胚層。它表達干細(xì)胞的特征性表面標(biāo)志物，具有干細(xì)胞的特性。羊膜間充質(zhì)干細(xì)胞的分裂增殖能力極強，并且可以分化為多種細(xì)胞。羊膜間充質(zhì)干細(xì)胞可以在體外誘導(dǎo)成骨細(xì)胞、脂肪細(xì)胞和軟骨細(xì)胞等[1]。與其他間充質(zhì)干細(xì)胞不同的是，羊膜間充質(zhì)干細(xì)胞不表達主要組織相容性復(fù)合物Ⅱ類分子，并且具有免疫調(diào)節(jié)的能力，因此，羊膜間充質(zhì)干細(xì)胞的移植不會產(chǎn)生很強的移植排斥反應(yīng)[2]。

如今，羊膜間充質(zhì)干細(xì)胞的移植已經(jīng)成功運用在許多疾病的動物模型中，例如：肝纖維化[3]和腎小球腎炎[4]等。此外，在肌萎縮側(cè)索硬化癥[5]中，羊膜間充質(zhì)干細(xì)胞分泌的細(xì)胞因子不僅可以降低損傷部位積累的炎癥反應(yīng)，還可以發(fā)揮營養(yǎng)作用。羊膜間充質(zhì)干細(xì)胞雖然在眾多疾病的動物模型中成功移植，但是有關(guān)臨床方面的研究還很少被報道。本文將對羊膜間充質(zhì)干細(xì)胞免疫調(diào)節(jié)做一綜述，為相關(guān)研究奠定理論基礎(chǔ)。

一、羊膜間充質(zhì)干細(xì)胞對單核巨噬細(xì)胞的調(diào)節(jié)

（一）細(xì)胞功能調(diào)節(jié)

羊膜間充質(zhì)干細(xì)胞能夠影響單核巨噬細(xì)胞的分化、增殖、趨化、抗原呈遞和分泌細(xì)胞因子等能力。

羊膜間充質(zhì)干細(xì)胞通過改變單核細(xì)胞表面抗原的表達，使要向M1型巨噬細(xì)胞分化的單核細(xì)胞轉(zhuǎn)變?yōu)镸2樣巨噬細(xì)胞[6]。在有利于向M2型細(xì)胞分化條件下，羊膜間充質(zhì)干細(xì)胞能夠使單核細(xì)胞保留M2樣巨噬細(xì)胞的特征，但是會使單核細(xì)胞提高CD23的表達和降低CD80的表達。雖然羊膜間充質(zhì)干細(xì)胞能夠影響單核細(xì)胞向巨噬細(xì)胞的分化，但是羊膜間充質(zhì)干細(xì)胞無法將已經(jīng)分化為M1型的巨噬細(xì)胞轉(zhuǎn)分化為M2型巨噬細(xì)胞[7]。

羊膜間充質(zhì)干細(xì)胞能抑制單核細(xì)胞的增殖能力。單核細(xì)胞在受到植物凝集素或者促分裂原刺激時，自身會進行增殖。單核細(xì)胞的這種增殖能力會被羊膜間充質(zhì)干細(xì)胞抑制，并且隨著共培養(yǎng)的羊膜間充質(zhì)干細(xì)胞數(shù)目的增多，這種抑制現(xiàn)象會更加明顯[8]。研究表明，羊膜間充質(zhì)干細(xì)胞能夠使脂多糖（lipopolysaccharide，LPS）誘導(dǎo)的單核細(xì)胞的細(xì)胞周期基本停滯在G0期[9]。羊膜間充質(zhì)干細(xì)胞通過下調(diào)與細(xì)胞周期相關(guān)的基因和細(xì)胞周期蛋白依賴性激酶2、4、6的表達，上調(diào)細(xì)胞周期負(fù)性調(diào)節(jié)蛋白如p15和p21，阻滯單核細(xì)胞的細(xì)胞周期在G0/G1期[10]。值得注意的是，羊膜間充質(zhì)干細(xì)胞抑制單核細(xì)胞的增殖，不嚴(yán)格依賴于細(xì)胞與細(xì)胞的接觸，主要由羊膜間充質(zhì)干細(xì)胞釋放的可溶性因子介導(dǎo)[9]。

羊膜間充質(zhì)干細(xì)胞能夠抑制巨噬細(xì)胞的趨化能力[11]。羊膜間充質(zhì)干細(xì)胞能改善結(jié)腸炎中單核細(xì)胞趨化因子-1（monocyte chemotactic protein 1，MCP-1）上調(diào)的不利影響，抑制巨噬細(xì)胞分泌MCP-1，從而使得MCP-1維持在一個較低的水平，減少巨噬細(xì)胞的浸潤[12]。在急性胰腺炎的小鼠模型中，羊膜間充質(zhì)干細(xì)胞的移植也會抑制巨噬細(xì)胞對胰腺的浸潤[13]。這些研究表明，羊膜間充質(zhì)干細(xì)胞能夠抑制巨噬細(xì)胞募集到炎癥部位，降低巨噬細(xì)胞的浸潤。

吞噬是巨噬細(xì)胞的另一個重要的功能[7]，羊膜間充質(zhì)干細(xì)胞能夠維持巨噬細(xì)胞的吞噬能力在特定的水平。在誘導(dǎo)單核細(xì)胞分化為M1型巨噬細(xì)胞的培養(yǎng)基中，羊膜間充質(zhì)干細(xì)胞能夠提高巨噬細(xì)胞的吞噬能力。相反，在誘導(dǎo)單核細(xì)胞分化為M2型巨噬細(xì)胞的培養(yǎng)基中，巨噬細(xì)胞的吞噬能力被羊膜間充質(zhì)干細(xì)胞抑制[14]。羊膜間充質(zhì)干細(xì)胞雖然維持了巨噬細(xì)胞的吞噬能力，但是卻降低巨噬細(xì)胞的抗原呈遞作用。羊膜間充質(zhì)干細(xì)胞通過抑制巨噬細(xì)胞呈遞抗原，抑制了CD4+T淋巴細(xì)胞的活化，降低了淋巴細(xì)胞內(nèi)的蛋白酶粒B的表達[7]。

在急性炎癥階段，巨噬細(xì)胞會通過腫瘤壞死因子 α（tumor necrosis factor-α，TNF-α） 和干擾素 γ（interferon-γ，IFN-γ）信號通路，產(chǎn)生炎癥信號，轉(zhuǎn)變?yōu)榻?jīng)典激活的M1表型，，分泌促進炎癥的細(xì)胞因子，比如白 介 素 -6（interleukin-6，IL-6），TNF-α 和白介素 -1β（interleukin-1β，IL-1β）。相比之下，M2型巨噬細(xì)胞通過分泌抗炎因子，比如白介素-10（interleukin-10，IL-10），轉(zhuǎn)化生長因子β（transform growth factor-β，TGF-β）等[15]。羊膜間充質(zhì)干細(xì)胞可以抑制LPS刺激下的單核細(xì)胞產(chǎn)生的一些促進炎癥因子，比如TNF-α、IL-6和IL-1β等，這種抑制作用隨共培養(yǎng)的羊膜間充質(zhì)干細(xì)胞數(shù)目的增多而增加，呈現(xiàn)劑量依賴性[16]。另一方面，羊膜間充質(zhì)干細(xì)胞能促進抗炎因子IL-10，TGF-β等的分泌[2]。實驗證實，部分羊膜間充質(zhì)干細(xì)胞通過抑制NF-κB活化和ERK和JNK磷酸化，下調(diào)促進炎癥基因的表達，上調(diào)抗炎基因的表達，從而改變巨噬細(xì)胞分泌的細(xì)胞因子[12,17]。

（二）調(diào)節(jié)機制

涉及到上述的機制研究并不是十分詳盡，以下對可能的一些機制進行歸納總結(jié)。羊膜間充質(zhì)干細(xì)胞既能夠通過細(xì)胞接觸，又可以通過分泌細(xì)胞因子來發(fā)揮上述的作用，但主要通過分泌的細(xì)胞因子發(fā)揮作用[8-9]。另外，細(xì)胞接觸也可能增強羊膜間充質(zhì)干細(xì)胞產(chǎn)生抑制性可溶性細(xì)胞因子，間接發(fā)揮作用[18]。

在與外周血單核細(xì)胞一起培養(yǎng)時，羊膜間充質(zhì)干細(xì)胞能夠分泌前列腺素 E2（prostaglandin E2，PGE2）、IL-6、肝細(xì)胞生長因子（hepatocyte growth factor，HGF）、吲哚胺 2,3雙加氧酶（indoleamine2.3-dioxygenase，IDO）、TGF-β 和可溶性人白細(xì)胞抗原-G（soluble human leukocyte antigen-G，sHLA-G）等[16,19-21]。Magatti等[7]和 Lange-Consiglio等[22]通過transwell系統(tǒng)和含有羊膜間充質(zhì)干細(xì)胞分泌物的條件培養(yǎng)基分別培養(yǎng)巨噬細(xì)胞，巨噬細(xì)胞的功能均被抑制，證實了上述分泌的細(xì)胞因子在羊膜間充質(zhì)干細(xì)胞對巨噬細(xì)胞的免疫調(diào)節(jié)中發(fā)揮作用。

羊膜間充質(zhì)干細(xì)胞的免疫抑制的作用主要是PGE2發(fā)揮主要作用。前列腺素E2是前列腺素家族中的一員。這種分子已被公認(rèn)為具有抗炎癥和免疫調(diào)節(jié)效應(yīng)[23]。炎性細(xì)胞因子（例如IL-1β）通過激活轉(zhuǎn)錄因子核因子κB，增加羊膜間充質(zhì)干細(xì)胞內(nèi)環(huán)氧合酶-2（cyclooxygenase-2，COX-2）的表達，進而促進PGE2的產(chǎn)生。Magatti等[7]人利用了COX-2的抑制劑——吲哚美辛，阻斷羊膜間充質(zhì)干細(xì)胞分泌PGE2，削弱了粒細(xì)胞-巨噬細(xì)胞集落刺激因子刺激下的巨噬細(xì)胞分泌炎癥因子的能力。羊膜間充質(zhì)干細(xì)胞釋放的PGE2通過結(jié)合巨噬細(xì)胞表面前列腺素受體EP2和EP4，繼而激活G蛋白，提高巨噬細(xì)胞內(nèi)cAMP的水平，巨噬細(xì)胞內(nèi)高濃度的cAMP會影響巨噬細(xì)胞的吞噬作用和促炎因子的分泌[24]。

此外，IL-6也在羊膜間充質(zhì)干細(xì)胞發(fā)揮免疫調(diào)節(jié)功能時發(fā)揮一定的作用。有研究報道，IL-6也可以促進巨噬細(xì)胞CD206和吞噬活性[25]，在阻斷羊膜間充質(zhì)干細(xì)胞產(chǎn)生IL-6的情況下，部分巨噬細(xì)胞分泌的炎癥因子（IL-1、TNF-α等）也有一定程度增加[7]。其他的羊膜間充質(zhì)干細(xì)胞分泌的細(xì)胞因子，例如IDO和HGF等，在羊膜間充質(zhì)干細(xì)胞的免疫抑制功能中發(fā)揮的作用很小[23]。

另一方面，羊膜間充質(zhì)干細(xì)胞發(fā)揮免疫抑制作用也可能是通過促進單核細(xì)胞的抗炎因子IL-10的分泌，間接發(fā)揮免疫抑制的作用。IL-10不僅可以抑制炎癥，還可以促進羊膜間充質(zhì)干細(xì)胞產(chǎn)生sHLA-G，sHLA-G可以作用在巨噬細(xì)胞上從而發(fā)揮免疫抑制的功能[18]。

以上就是羊膜間充質(zhì)干細(xì)胞對巨噬細(xì)胞發(fā)揮免疫抑制的一些可能的機制，但是在不同的疾病模型中，羊膜間充質(zhì)干細(xì)胞發(fā)揮作用的機制各不相同，主要取決于疾病發(fā)病的特點和作用于何種細(xì)胞。

二、羊膜間充質(zhì)干細(xì)胞對T淋巴細(xì)胞的調(diào)節(jié)作用

（一）細(xì)胞功能調(diào)節(jié)

羊膜間充質(zhì)干細(xì)胞能夠影響T淋巴細(xì)胞分化，增殖和分泌細(xì)胞因子。

羊膜間充質(zhì)干細(xì)胞影響了T淋巴細(xì)胞的分化。羊膜間充質(zhì)干細(xì)胞顯著降低了Th1數(shù)目，但是不影響Th2亞群數(shù)目和表面標(biāo)志物的表達。不僅如此，羊膜間充質(zhì)干細(xì)胞能夠誘導(dǎo)調(diào)節(jié)性T淋巴細(xì)胞（regulatory T lymphocyte，Treg）的產(chǎn)生，提示羊膜間充質(zhì)干細(xì)胞能夠通過改變T淋巴細(xì)胞亞群的比例來發(fā)揮免疫調(diào)節(jié)功能[25]。

羊膜間充質(zhì)干細(xì)胞能夠抑制T淋巴細(xì)胞的增殖。當(dāng)T淋巴細(xì)胞與羊膜間充質(zhì)干細(xì)胞共同培養(yǎng)，或者用培養(yǎng)過羊膜間充質(zhì)干細(xì)胞的培養(yǎng)基培養(yǎng)T淋巴細(xì)胞時，在有凝集素或者絲裂原激活的情況下，輔助性T淋巴細(xì)胞和細(xì)胞毒性T淋巴細(xì)胞的增殖能力被抑制，并且這種抑制的效果呈現(xiàn)劑量依賴[26]。在羊膜間充質(zhì)干細(xì)胞和T淋巴細(xì)胞共培養(yǎng)中，羊膜間充質(zhì)干細(xì)胞能誘導(dǎo)初始T淋巴細(xì)胞和Treg細(xì)胞數(shù)目的增加，減少記憶T淋巴細(xì)胞數(shù)目。羊膜間充質(zhì)干細(xì)胞還能誘導(dǎo)T淋巴細(xì)胞向Th2和Th17亞群極化，抑制T淋巴細(xì)胞向Th1亞群極化[27]。

羊膜間充質(zhì)干細(xì)胞能夠抑制T淋巴細(xì)胞分泌促炎因子，比如與Th1相關(guān)的TNFα、IFNγ和IL-1β，與Th2相關(guān)的IL-5和IL-6，與Th19相關(guān)的IL-9和與Th17相關(guān)的IL-17A和IL-22[28]。Kang等[18]人證實，當(dāng)外周血單個核細(xì)胞（peripheral blood mononuclear cell，PBM）與羊膜間充質(zhì)干細(xì)胞共培養(yǎng)時，PBMC產(chǎn)生的IFN-γ和IL-17顯著降低，IL-10和TGF-β的產(chǎn)生量增加。

（二）調(diào)節(jié)機制

羊膜間充質(zhì)干細(xì)胞對T淋巴細(xì)胞的免疫抑制作用與兩種機制有關(guān)：一種是通過可溶性細(xì)胞因子[30]，如IDO、PGE2、TGF-β、sHLA-G等；另一種是通過細(xì)胞與細(xì)胞的接觸[31]?，F(xiàn)認(rèn)為是以前者為主。

羊膜間充質(zhì)干細(xì)胞主要是通過旁分泌誘導(dǎo)對T細(xì)胞的免疫調(diào)節(jié)。研究說明，羊膜間充質(zhì)干細(xì)胞通過分泌某種低分子量、非蛋白質(zhì)、熱穩(wěn)定的化合物來發(fā)揮對T淋巴細(xì)胞的調(diào)節(jié)作用。其中，前列腺素是羊膜間充質(zhì)干細(xì)胞發(fā)揮免疫調(diào)節(jié)功能的關(guān)鍵效應(yīng)分子之一[23]。其他一些羊膜間充質(zhì)干細(xì)胞的分泌物，如TGF-β，HGF和IDO在培養(yǎng)羊膜間充質(zhì)干細(xì)胞的上清液中能被檢測到，也可能是羊膜間充質(zhì)干細(xì)胞發(fā)揮對T淋巴細(xì)胞免疫調(diào)節(jié)功能的重要分子[18]。這些分子直接結(jié)合到T淋巴細(xì)胞表面受體，激活相應(yīng)的信號通路，直接影響了T淋巴細(xì)胞的功能。

三、羊膜間充質(zhì)干細(xì)胞對樹突狀細(xì)胞的調(diào)節(jié)作用

羊膜間充質(zhì)干細(xì)胞影響了樹突狀細(xì)胞表型。羊膜間充質(zhì)干細(xì)胞通過抑制單核細(xì)胞獲得樹突狀細(xì)胞的表面標(biāo)志，例如 ：特殊標(biāo)志物（CD1a）、共激分子（CD80和 CD86）、激活分子（CD83和CD197）和HLA-DR等，從而影響了單核細(xì)胞向樹突狀細(xì)胞的分化[9,32]。這些不能分化為樹突狀譜系的單核細(xì)胞，轉(zhuǎn)而分化為一種與M2巨噬細(xì)胞接近的巨噬細(xì)胞類型[33]，并且Dabrowski等[21]人證明，即使分離與羊膜間充質(zhì)干細(xì)胞共培養(yǎng)的單核細(xì)胞后，用LPS的刺激，也不能分化為樹突狀細(xì)胞，說明羊膜間充質(zhì)干細(xì)胞誘導(dǎo)單核細(xì)胞的分化具有不可逆性。

羊膜間充質(zhì)干細(xì)胞也影響了樹突狀細(xì)胞的功能[14]。與羊膜間充質(zhì)干細(xì)胞一起培養(yǎng)時，樹突狀細(xì)胞只能誘導(dǎo)較低水平的T淋巴細(xì)胞的增殖，說明樹突狀細(xì)胞的抗原呈遞作用被削弱。不僅如此，羊膜間充質(zhì)干細(xì)胞阻滯樹突狀細(xì)胞周期中的G0期，抑制樹突狀細(xì)胞的增殖。在樹突狀分泌細(xì)胞因子的功能方面，羊膜間充質(zhì)干細(xì)胞能夠阻斷樹突狀細(xì)胞分泌IL-12p70 和 TNF-α 等[33]。

羊膜間充質(zhì)干細(xì)胞對樹突狀細(xì)胞的免疫調(diào)節(jié)現(xiàn)象出現(xiàn)在細(xì)胞共培養(yǎng)系統(tǒng)和transwell系統(tǒng)中[9]，提示羊膜間充質(zhì)干細(xì)胞分泌的細(xì)胞因子參與了羊膜間充質(zhì)干細(xì)胞對樹突狀細(xì)胞的免疫調(diào)節(jié)中[34]。

四、展望

干細(xì)胞移植為許多疾病提供了一種新的治療思路和方案，但由于干細(xì)胞難以獲得以及免疫排斥的原因，干細(xì)胞移植沒有在臨床中普遍使用。不同于其他的干細(xì)胞來源，羊膜間充質(zhì)干細(xì)胞具有容易獲得、能誘導(dǎo)免疫耐受和沒有倫理障礙等優(yōu)點，這將使得羊膜間充質(zhì)干細(xì)胞移植的臨床前景十分廣闊。羊膜間充質(zhì)干細(xì)胞移植已經(jīng)在許多疾病動物模型中被成功驗證，羊膜間充質(zhì)干細(xì)胞移植的臨床研究也正進一步開展中。隨著研究的深入，在不久的將來，羊膜間充質(zhì)干細(xì)胞將會應(yīng)用到臨床患者的治療中。

1 Chang YJ, Hwang SM, Tseng CP, et al. Isolation of mesenchymal stem cells with neurogenic potential from the mesoderm of the amniotic membrane[J]. Cells Tissues Organs, 2010, 192(2):93-105.

2 Cargnoni A, Piccinelli EC, Ressel L, et al. Conditioned medium from amniotic membrane-derived cells prevents lung fi brosis and preserves blood gas exchanges in bleomycin-injured mice-specificity of the effects and insights into possible mechanisms[J]. Cytotherapy, 2014,16(1):17-32.

3 Sant'anna LB, Cargnoni A, Ressel L, et al. Amniotic membrane application reduces liver fi brosis in a bile duct ligation rat model[J].Cell Transplant, 2011, 20(3):441-453.

4 Tsuda H, Yamahara K, Ishikane S, et al. Allogenic fetal membranederived mesenchymal stem cells contribute to renal repair in experimental glomerulonephritis[J]. Am J Physiol Renal Physiol, 2010,299(5):F1004-F1013.

5 Sun H, Hou Z, Yang H, et al. Multiple systemic transplantations of human amniotic mesenchymal stem cells exert therapeutic effects in an ALS mouse model[J]. Cell Tissue Res, 2014, 357(3):571-582.

6 何妲, 彭琳, 黃生建, 等. 三種成體干細(xì)胞對脂多糖誘導(dǎo)RAW264.7細(xì)胞炎癥狀態(tài)的影響[J]. 南方醫(yī)科大學(xué)學(xué)報, 2014 (11):1627-1631.

7 Magatti M, Vertua E, De Munari S, et al. Human amnion favours tissue repair by inducing the M1-to-M2 Switch and enhancing M2 macrophage features[J]. J Tissue Eng Regen Med, 2016 .

8 Wolbank S, Peterbauer A, Fahrner MA, et al. Dose-dependent immunomodulatory effect of human stem cells from amniotic membrane: A comparison with human mesenchymal stem cells from adipose tissue[J]. Tissue Eng, 2007, 13(6):1173-1183.

9 Magatti M, De Munari S, Vertua E, et al. Amniotic mesenchymal tissue cells inhibit dendritic cell differentiation of peripheral blood and amnion resident monocytes[J]. Cell Transplant, 2009, 18(8):899-914.

10 Magatti M, De Munari S, Vertua E, et al. Amniotic membrane-derived cells inhibit proliferation of cancer cell lines by inducing cell cycle arrest[J]. J Cell Mol Med, 2012, 16(9):2208-2218.

11 Tan JL, Chan ST, Wallace EM, et al. Human amnion epithelial cells mediate lung repair by directly modulating macrophage recruitment and polarization[J]. Cell Transplant, 2014, 23(3):319-328.

12 Onishi R, Ohnishi S, Higashi R, et al. Human Amnion-Derived mesenchymal stem cell transplantation ameliorates dextran sulfate Sodium-Induced severe colitis in rats[J]. Cell Transplant, 2015,24(12):2601-2614.

13 Kawakubo K, Ohnishi S, Fujita H, et al. Effect of fetal Membrane-Derived mesenchymal stem cell transplantation in rats with acute and chronic pancreatitis[J]. Pancreas, 2016, 45(5):707-713.

14 Kronsteiner B, Peterbauer-Scherb A, Grillari-Voglauer R, et al. Human mesenchymal stem cells and renal tubular epithelial cells differentially influence monocyte-derived dendritic cell differentiation and maturation[J]. Cell Immunol, 2011, 267(1):30-38.

15 He H, Zhang S, Tighe S, et al. Immobilized heavy chain-hyaluronic acid polarizes lipopolysaccharide-activated macrophages toward M2 phenotype[J]. J Biol Chem, 2013, 288(36):25792-25803.

16 Yamahara K, Harada K, Ohshima M, et al. Comparison of angiogenic,cytoprotective, and immunosuppressive properties of human amnionand chorion-derived mesenchymal stem cells[J]. PLoS One, 2014, 9(2):e88319.

17 Shu J, He X, Zhang L, et al. Human amnion mesenchymal cells inhibit lipopolysaccharide-induced TNF-α and IL-1β production in THP-1 cells[J]. Biol Res, 2015, 48(1):69.

18 Kang JW, Koo HC, Hwang SY, et al. Immunomodulatory effects of human amniotic membrane-derived mesenchymal stem cells[J]. J Vet Sci, 2012, 13(1):23-31.

19 Li C, Zhang W, Jiang X, et al. Human-placenta-derived mesenchymal stem cells inhibit proliferation and function of allogeneic immune cells[J]. Cell Tissue Res, 2007, 330(3):437-446.

20 Toda A, Sawada K, Fujikawa T, et al. Targeting inhibitor of κB kinase β prevents In fl ammation-Induced preterm delivery by inhibiting IL-6 production from amniotic cells[J]. Am J Pathol, 2016, 186(3):616-629.

21 Dabrowski FA, Burdzinska A, Kulesza A, et al. Mesenchymal stem cells from human amniotic membrane and umbilical cord can diminish immunological response in an in vitro allograft model[J]. Gynecol Obstet Invest, 2017, 82(3):267-275.

22 Lange-Consiglio A, Rossi D, Tassan S, et al. Conditioned medium from horse amniotic membrane-derived multipotent progenitor cells:immunomodulatory activity in vitro and first clinical application in tendon and ligament injuriesin vivo[J]. Stem Cells Dev, 2013,22(22):3015-3024.

23 Rossi D, Pianta S, Magatti M, et al. Characterization of the conditioned medium from amniotic membrane cells: prostaglandins as key effectors of its immunomodulatory activity[J]. PLoS One, 2012, 7(10):e46956.

24 Zaslona Z, Serezani CH, Okunishi K, et al. Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling[J]. Blood, 2012, 119(10):2358-2367.

25 Deng W, Chen W, Zhang Z, et al. Mesenchymal stem cells promote CD206 expression and phagocytic activity of macrophages through IL-6 in systemic lupus erythematosus[J]. Clin Immunol, 2015,161(2):209-216.

26 宋潔, 高雅, 卓偉彬, 等. 人羊膜間充質(zhì)干細(xì)胞與骨髓間充質(zhì)干細(xì)胞對外周血淋巴細(xì)胞的免疫調(diào)節(jié)作用比較[J]. 南方醫(yī)科大學(xué)學(xué)報,2017, 37(6):780-785.

27 La Rocca G, Lo Iacono M, Corsello T, et al. Human wharton's jelly mesenchymal stem cells maintain the expression of key immunomodulatory molecules when subjected to osteogenic,adipogenic and chondrogenic differentiation in vitro: new perspectives for cellular therapy[J]. Curr Stem Cell Res Ther, 2013, 8(1):100-113.

28 Mareschi K, Castiglia S, Sanavio F, et al. Immunoregulatory effects on T lymphocytes by human mesenchymal stromal cells isolated from bone marrow, amniotic fluid, and placenta[J]. Exp Hematol, 2016,44(2):138-150.e1.

29 Pianta S, Bonassi Signoroni P, Muradore I, et al. Amniotic membrane mesenchymal cells-derived factors skew T cell polarization toward Treg and downregulate Th1 and Th17 cells subsets[J]. Stem Cell Rev,2015, 11(3):394-407.

30 Xue Y, Miao Z, Sun H. Effects of human amniotic mesenchymal stromal cells on rabbit T-cell responses in a xenolymphocyte reaction assay[J]. Exp Clin Transplant, 2014, 12(3):253-260.

31 Sato K, Ozaki K, Oh I, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells[J].Blood, 2007, 109(1):228-234.

32 Pianta S, Magatti M, Vertua E, et al. Amniotic mesenchymal cells from pre-eclamptic placentae maintain immunomodulatory features as healthy controls[J]. J Cell Mol Med, 2016, 20(1):157-169.

33 Magatti M, Caruso M, De Munari S, et al. Human amniotic Membrane-Derived mesenchymal and epithelial cells exert different effects on Monocyte-Derived dendritic cell differentiation and function[J]. Cell Transplant, 2015, 24(9):1733-1752.

34 Banas R, Miller C, Guzik L, et al. Amnion-derived multipotent progenitor cells inhibit blood monocyte differentiation into mature dendritic cells[J]. Cell Transplant, 2014, 23(9):1111-1125.

2017-06-11）

（本文編輯：蔡曉珍）

歐陽文，廖正權(quán)，夏增飛，等.羊膜間充質(zhì)干細(xì)胞的免疫調(diào)節(jié)功能研究進展[J/CD].中華細(xì)胞與干細(xì)胞雜志（電子版），2017，7（5）：313-316.

Progress of immune regulatory function of Amniotic mesenchymal stem cells

Ouyang Wen1,2,Liao Zhengquan1,2, Xia Zengfei1,2, GaoYa3, Guo Yanwu1,2, Sun Haitao1,2.1Department of neurosurgery,Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China;2The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510282, China;3Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

Sun Haitao, Email: msunhaitao1988@126.com

The amniotic mesenchymal stem cell is a stem cell derived from the amnion.Compared with other sources of stem cells, the amniotic mesenchymal stem cell possesses the characteristics of low immunogenicity and immunosuppression, for which makes the side effect of transplantation of the amniotic mesenchymal stem cell relatively smaller. The efficient effects of the treatment have been shown in some diseases, which are associated with inflammation. Relevant clinical trials were carried out. Although some of the mechanisms of immunomodulation of amniotic mesenchymal stem cell has been found, but they are not completely clarified. This review outlines the immune regulatory function of the amniotic mesenchymal stem cell, which provides some information for the further studies.

Amniotic mesenchymal stem cell; Immunomodulation; Macrophage; T cell; Dendritic cell

10.3877/cma.j.issn.2095-1221.2017.05.011

國家自然科學(xué)基金（81671193，81701243）；廣東省自然科學(xué)基金（2014A030310373）；廣州市珠江科技新星專項（201710010047）；中國科學(xué)院再生生物學(xué)重點實驗室開放課題資助（KLRB201503）

510282 廣州，南方醫(yī)科大學(xué)珠江醫(yī)院神經(jīng)外科1；510282廣州，南方醫(yī)科大學(xué)第二臨床醫(yī)學(xué)院2；510515 廣州，南方醫(yī)科大學(xué)南方醫(yī)院血液科3

孫海濤，Email：msunhaitao1988@126.com