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   复旦学报(医学版)  2021, Vol. 48 Issue (6): 819-826      DOI: 10.3969/j.issn.1672-8467.2021.06.015
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人羊膜上皮细胞在妇产科相关疾病中的应用及研究进展
王璐璐  (综述), 赖东梅  (审校)     
上海交通大学医学院附属国际和平妇幼保健院妇科-上海市胚胎源性疾病重点实验室 上海 200030
摘要:人羊膜上皮细胞(humanamniotic epithelial cells,hAECs)来源于羊膜的最内层,由胚泡内细胞团发育而来。hAECs可易分离,并具有部分胚胎干细胞(embryonic stem cells,ESCs)特性,在特定条件下,hAECs能分化为3个胚层的不同类型的细胞;hAECs还具有免疫原性低、免疫调节性和非致瘤性等优点。另外,hAECs可分泌多种细胞因子,如生长因子、神经营养因子和抗炎因子等。越来越多的研究表明,hAECs有助于修复患病受损的组织和器官并促进组织再生,因此具有广泛的应用前景。本文就hAECs在妇产科相关疾病(包括早发性卵巢功能不全、子宫内膜损伤、妇科恶性肿瘤、复发性流产)中的应用作一简要阐述。
关键词人羊膜上皮细胞(hAEC)    卵巢功能    子宫内膜损伤    妇科恶性肿瘤    复发性流产(RSA)    
Research progress and application of human amniotic epithelial cells in obstetrical and gynecological diseases
WANG Lu-lu , LAI Dong-mei     
Department of Gynecology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine-Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China
Abstract: Human amniotic epithelial cells (hAECs) are originated from the innermost layer of the amniotic membrane and derivated from the inner cell mass of the blastocyst. hAECs are easily isolated from amniotic membrane, which possess characteristics of embryonic stem cells (ESCs) and can differentiate into the three germ layers under specific culture conditions. hAECs also have many excellent properties such as low immunogenicity, immunomodulatory and non-tumorigenicity. Moreover, hAECs can secrete a wide spectrum of cytokine, including growth factors, neurotrophic factors and anti-inflammatory factors. A growing body of research indicates that hAECs can help to restore the function of damaged tissues and organs. Therefore, hAECs have broad application prospects. This review focuses on the current research advances of the application of hAECs in obstetrics and gynecology-related diseases, including premature ovarian insufficiency, endometrial injury, gynecologic malignancies, and recurrent spontaneous abortion.
Key words: human amniotic epithelial cell (hAECs)    ovarian function    intrauterine adhesions    gynecologic malignancies    recurrent spontaneous abortion (RSA)    

干细胞可用于治疗多种严重疾病,主要基于两个特性,即多能性和免疫调节性。多能性赋予干细胞分化为所需细胞类型的能力,从而用于细胞替代治疗;而免疫调节性可用于控制炎症反应和组织免疫排斥反应[1]。人胎盘中可分离出多种干细胞,而人羊膜上皮细胞(human amniotic epithelial cells,hAECs)与其他类型胎盘干细胞不同,hAECs来自外胚层,并在整个妊娠过程中保持分化潜能,属于围产期干细胞之一[2]。hAECs在体内外均具有多能性和免疫调节作用,是干细胞治疗和再生医学领域的理想种子细胞[3]。近年来,hAECs用于妇产科相关疾病的治疗逐渐成为研究的热点且相关主题的最新进展综述较少,本文就hAECs在妇产科相关疾病的治疗中的应用进行综述。

hAECs的生理学特点    人羊膜(amniotic membrane,AM)是胎盘最接近胎儿的一层,它是由上皮和以结缔组织为主要成分的基质层组成的无血管膜,该层在怀孕期间包裹着胎儿和羊水,使发育中的胚胎免受来自周围环境的各种刺激作用[2]。因此,AM在胚胎的发育和保护中起着重要作用。AM属于胎儿附属物,是胎盘发育的早期产物,主要由上皮层、基底膜、致密层、纤维母细胞层和海绵层组成。AM主要包含两种来自不同胚胎起源的多能干细胞,即人羊膜间充质干细胞(human amniotic mesenchymal stem cells,hAMSCs)和hAECs[4]。hAMSCs来源于胚胎中胚层,稀疏的分布在羊膜上皮下的基质中,而hAECs是从原肠胚形成前的外胚层衍生而来,形成AM最内层,是与羊水直接接触的连续单层。两者都保留了干细胞样特性,均具有向3个胚层分化的能力[3]。hAECs和hAMSCs可以通过差异酶消化分别从羊膜中分离出来,即使用低速胰蛋白酶-胶原酶消化羊膜组织,并且可以通过显微镜和流式细胞仪来鉴别[5]。在显微镜下,新鲜分离的hAECs是中等大小的圆形细胞,有一个中心或偏心的细胞核,细胞核内有1个或2个核仁,细胞质较丰富且常空泡化,而hAMSCs呈纺锤形或成纤维细胞样形态。通过流式细胞仪鉴定表征分析,从AM中分离的hAECs明显表达上皮标志物角蛋白CK19,不表达间充质细胞标志物波形蛋白,而hAMSCs表达波形蛋白,不表达角蛋白CK19,且hAMSCs中CD90和CD44的表达水平高于hAECs,而hAECs中CD73则高于hAMSCs[6]。尽管许多研究表明胎盘中可以分离出多种干细胞,但羊膜来源的细胞与胚胎干细胞(embryonic stem cells,ESCs)具有更紧密的组织学关系[2]。此外,hAECs上表达ESCs表面选择性表达分子,即阶段性特异性胚胎抗原(SSEA3/4)和肿瘤排斥抗原(TRA1-60/1-81),且ESCs标记物在hAECs中的表达量都高于在hAMSCs中的表达量高,表明hAECs可能处于更早的未分化状态[6]。此外,hAECs还表达自我更新和分化潜能所需的多能干细胞特异性转录因子,如八聚体结合蛋白4、性别决定区域相关的HMG-box基因2(SOX-2)和Nanog[7]。在不同的培养和诱导条件下,hAECs表现出向3个胚层不同类型细胞的分化的能力,如心肌细胞[8]、神经元[9]、胰腺α和β细胞[10-11]、肝细胞[12]以及卵巢颗粒细胞[13]等。此外,hAECs能够分泌多种细胞因子,如生长因子、神经营养因子和抗炎因子等,来促进受损组织的修复[14]

许多研究表明人AM中具有免疫调节功能的细胞可参与维持胎儿耐受性,且AM具有低免疫原性的特点[2]。胎盘的作用之一是形成母胎界面,在怀孕期间保护胎儿免受母体免疫识别攻击和包括感染在内各种伤害。据报道,胎儿的这种“耐受性”由特定家族的人类白细胞抗原(human leucocyte antigen,HLA)Ⅰb类的表达引起,尤其是HLA-G的表达和分泌被认为是介导胎儿耐受性的关键因素[15],并且HLA Ⅰb类表达和分泌增加有利于提高同种异体移植的耐受性,从而降低急性排斥反应的发生率[16]。研究表明,hAECs表达HLA Ⅰ类抗原分子,但不表达HLA Ⅱ类抗原(HLA-DR)或共刺激因子CD80和CD86,从而降低了hAECs移植后的免疫排斥反应,且hAECs表达和分泌HLA-G的水平在用IFN-γ处理后会增加[17],因此hAECs参与维持胎儿耐受性。另外,体外培养的hAECs可成功移植到裸露的兔角膜上而不发生组织排斥[18]。总之,来源于AM的hAECs参与维持胎儿耐受性,具有免疫原性低的特点。

据报道,hAECs可分泌大量的抗炎蛋白,如激活素a、IL-1的受体拮抗剂(IL-1-Ra)和IL-10,沉积在羊膜基质内,抵御外来病原体的干扰[4]。另外,将hAECs移植到博来霉素诱导的小鼠肺损伤模型体内,可以减少肺内转化生长因子-β、IL-1和IL-6等炎性因子的表达,减轻肺纤维化,促进肺损伤的修复[19]。hAECs还表达凋亡诱导基因FasLTNFTRAIL,促进白细胞凋亡[20]。总之,hAECs具有免疫调节性,在母体和胎儿之间起到免疫屏障作用,同时对病原体产生适当的防御功能,从而保护胎儿免受子宫内病原体的侵害。此外,hAECs还具有非致瘤性的优点[3]。端粒酶是一种在不断增殖细胞和肿瘤细胞中高表达的酶[21]。与hES不同,hAECs不表达端粒酶活性,在体外增殖过程中始终保持正常核型,并维持未分化状态[3]。有研究表明,将新鲜分离的hAECs注射入严重联合免疫缺陷(severe combined immunodeficiency,SCID)模型小鼠睾丸中,移植后10周内均未发现肿瘤形成的证据[22]

由于hAECs具有多潜能干细胞特性、免疫原性低、免疫调节性和非致瘤性等特点,已被广泛应用于多种疾病的治疗研究,包括眼科疾病、肺纤维化、肝脏疾病、中枢神经系统损伤等[3]。越来越多的研究将hAECs应用于妇产科相关疾病治疗。

hAECs对卵巢功能的修复作用    早发性卵巢功能不全(premature ovarian insufficiency,POI)是女性常见疾病之一。POI主要特征是女性40岁之前出现雌激素不足或缺乏、促性腺激素水平升高,出现闭经,不孕和绝经前综合症,由于雌激素水平低下,导致心脑血管疾病、骨质疏松症等风险显著上升[23]。已知POI的病因包括遗传性、医源性、自身免疫性、环境污染等,但绝大多数病因不明。POI发生后,激素替代疗法主要用于补充体内缺乏的雌激素,但不能恢复卵巢功能[24]。近年来,人们尝试采用各种干细胞进行卵巢功能的修复,如ESCs、脂肪来源的间充质干细胞、人脐带来源的间充质干细胞、诱导多能干细胞、精原干细胞、卵巢干细胞等[25]。人AM来源的干细胞成本低,易获取,创伤小,且hAECs表现出低免疫原性、非致瘤性和多向分化的能力,已成为治疗POI的理想候选细胞。研究表明,在含有血清替代品补充剂(serum substitute supplement,SSS)的培养基中培养的hAECs可以分化为卵母细胞样细胞并表达生殖细胞特异性标志物[26],且在体外人卵泡液诱导下hAECs可分化为生殖细胞,形成卵泡样结构[27]。我们课题组将荧光标记的hAECs注射入POI模型小鼠体内,显示hAECs迁移至小鼠卵巢并分化为颗粒细胞,在接受hAECs移植治疗的POI模型小鼠卵巢中,卵巢功能标记物抗苗勒氏激素表达水平明显(anti-Müllerian hormone,AMH)升高[13],经过维生素C预处理的hAECs可发挥更好的修复作用[28]。颗粒细胞是卵巢微环境的重要组成部分,在调节生殖卵巢生理(包括排卵和黄体退化)中起关键作用,hAECs显著抑制TNF-α介导的颗粒细胞凋亡,并减少受化学损伤卵巢的炎症反应,促进各级卵泡数增加并改善卵巢功能[29]。越来越多的研究表明,干细胞移植可通过分泌多种营养和免疫调节因子来重塑受损组织中的局部微环境,从而修复受损细胞和组织,并且这些营养因子和免疫调节因子可从无血清条件培养基中获取[30]。hAECs条件培养基(hAECs conditioned medium,hAEC-CM)中可检测到分泌的细胞因子,且这些细胞因子可能在血管生成、免疫反应、细胞周期和细胞凋亡等生物学过程中起作用。我们课题组将hAEC-CM注射到POI模型小鼠单侧卵巢中,卵巢中可观察到次要和成熟卵泡的数量显著上升,以及卵泡生长相关基因表达上调。在体外实验中发现,hAECs以旁分泌方式显著抑制原代颗粒-叶黄素细胞内化疗诱导的细胞凋亡并激活颗粒细胞的TGF-β/Smad信号通路[31],TGF-β超家族对卵巢的卵泡发育和功能恢复过程起重要作用,如调节卵泡发育、卵泡募集、排卵和黄素化等[32],并且hAEC-CM可以促进受伤卵巢的血管生成,并提高共培养系统中人脐静脉内皮细胞(human umbilical vein endothelial cells,hUVECs)成管能力[31-33]。这些研究表明,hAECs也可通过旁分泌产生的细胞因子来改善受损的卵巢微环境,从而抑制化学疗法诱导的细胞凋亡,促进血管生成和调节各级卵泡发育。此外,microRNA在卵泡发育过程中和POI发病机理中发挥重要作用[34],hAECs衍生的外泌体可通过转移microRNA对抗颗粒细胞凋亡来恢复化疗诱导的POI模型小鼠的卵巢功能[35]。我们课题组为了提高hAECs的归巢率和存活率以更好地修复受损的卵巢功能,将hAECs或hAEC-CM包裹在海藻酸钠生物玻璃(sodium alginate-bioglass,SA-BG)中,原位移植到卵巢上,发现SA-BG包裹的hAECs或CM可以通过保护颗粒细胞功能和促进卵巢血管生成,更好地修复受损的卵巢功能[36]。我们课题组还发现hAECs的免疫调节机制在卵巢功能修复中也发挥重要作用,hAECs可通过上调脾脏中的Treg细胞来恢复自身免疫性卵巢疾病模型小鼠的卵巢功能,并通过旁分泌方式调节卵巢中被激活的巨噬细胞的功能来减少炎症反应[37]。总之,hAECs可通过多种途径修复受损的卵巢功能。

hAECs对子宫内膜损伤和子宫瘢痕的修复作用    子宫内膜分为功能层和基底层,功能层在每个周期中通过生长、转化、剥脱和再生修复等一系列过程不断循环再生。随着人工流产、宫腔镜手术等增多,子宫内膜损伤越来越常见[38]。轻度损伤可触发局部炎性反应,促使上皮细胞再生,使子宫内膜达到无纤维瘢痕修复。重度损伤可累及子宫基底层,使子宫内膜细胞减少,腺体数量减少,失去正常的分泌功能,炎症细胞浸润吞噬上皮细胞,间质外露,间质细胞纤维活性增加,子宫内膜功能层和基底层失去正常界限,形成上皮再生障碍,无法对激素刺激产生应答,子宫内膜纤维粘连增生,纤维粘连间质中缺乏血管形成瘢痕,引起宫腔部分或完全纤维化,最终导致宫腔缩窄、扭曲甚至宫腔消失,形成宫腔粘连(intrauterine adhesions,IUA),即Asheman综合征,造成月经过少、闭经、不孕症、反复流产、慢性盆腔痛等问题,严重困扰患者,至今仍无有效的预防和治疗措施[39]。IUA的治疗措施主要聚焦于重建正常的子宫结构并恢复子宫正常功能,宫腔镜粘连溶解术治疗及术后放置球囊并结合激素疗法是目前临床上治疗IUA的主要方法,但效果欠佳且复发率高[39]。近年来应用外源性干细胞移植来改善子宫内膜损伤,为临床治疗重度子宫内膜损伤以获得妊娠机会提供了新的思路,如使用骨髓来源的间充质干细胞、子宫内膜干细胞、经血干细胞、脐带干细胞和脂肪干细胞等进行移植都可以帮助子宫内膜再生[40]。联合应用雌激素和子宫内膜干细胞治疗IUA可使受损的子宫内膜再生并逆转纤维化,改善子宫内膜微环境并恢复子宫内膜功能,显著提高了IUA的治疗效果[41]。子宫内膜损伤模型大鼠采用脂肪干细胞移植治疗后,受损的子宫内膜微血管密度、宫内膜厚度和腺体都明显增加,且生育能力得到改善[42]。另一方面,脂肪干细胞移植可能会促进癌细胞生长,子宫内膜干细胞与多种妇科疾病的发病机制有关,如子宫内膜癌、子宫内膜增生、子宫内膜异位症、子宫内腺肌病等,干细胞的致瘤性,免疫原性等限制了干细胞在子宫内膜修复领域的应用。相比而言,来源于人AM的hAECs在非创伤性取材、低免疫原性和非致瘤性等方面具有极大优势。我们课题组研究发现,hAECs移植治疗机械损伤建立的IUA模型小鼠后,受损子宫内膜中血管内皮生长因子(vascular endothelial growth factor,VEGF)、增殖细胞核抗原和雌激素受体的表达水平增加,即血管生成能力和基质细胞增殖能力得到改善,促进子宫内膜增厚、内膜腺体增加、胶原沉积减少及产生更多微血管。子宫内膜形态得到改善,从而使得IUA模型小鼠的妊娠率和产仔数增加[43]。同时,也有研究表明,经过hAECs移植治疗的IUA模型鼠的促胶原沉积的信号分子表达明显抑制,如α-SMA、TGF-β1和TGF-β2等,但抗纤维化分子TGF-β3在治疗组中表达水平显著上调[44]。此外,IUA模型小鼠的子宫内膜基质细胞中存在自噬抑制现象,自噬是细胞面对环境压力的一种为了自我保护而主动降解的过程,即分解衰老的细胞器并在缺乏营养时提供能量[45],而在体外hAECs与子宫内膜基质细胞的共培养系统中,观察到hAECs可以激活受损的子宫内膜基质细胞中的自噬,因此,hAECs可通过激活子宫内膜基质细胞的自噬来促进子宫内膜的修复[43]

子宫瘢痕憩室(cesarean scar defect,CSD)是剖宫产术后的常见远期并发症,定义为剖宫产术子宫瘢痕因愈合不良而导致子宫肌层停止生长,子宫瘢痕处肌层变薄,形成一个与宫腔相通的凹陷或腔隙[46]。随着剖宫产的增加,CSD持续上升,世界范围内CSD的患病率达45.6%~64.5%[47]。CSD可引起月经期延长、月经间期流血、慢性盆腔痛、经期腹痛等,此外还可引起继发性不孕、疤痕妊娠、前置胎盘、子宫破裂等产科并发症。目前对于改善CSD患者的临床症状或妊娠结局的最佳治疗方法尚无共识。我们课题组在体外构建了大鼠剖宫产憩室模型,并且将hAECs注射到子宫瘢痕周围,发现hAECs可通过上调VEGFA促进血管生成和上调基质金属蛋白酶-8(matrix metalloproteinase-8,MMP-8)减少胶原沉积,从而对子宫瘢痕进行修复,同时改善妊娠结局[48]。总之,hAECs的移植治疗可以抑制子宫内膜纤维化的进展,并促进子宫内膜血管生成和再生,从而修复子宫内膜损伤,同时也能通过促进瘢痕血管生成和降解瘢痕胶原来修复CSD。

hAECs的抗肿瘤作用    hAECs除了具有自我更新和分化为各种组织器官的能力,还具有治疗癌症的潜力,主要通过调节血管生成和分泌细胞毒性的细胞因子来发挥抗肿瘤作用。血管生成是胚胎发育、正常生长和组织修复的重要生理过程,血管生成在分子水平上受到严格调节。血管生成失调发生在各种病理组织中,也是癌症的基本病理特征之一[49]。肿瘤血管生成对于向生长中的肿瘤输送氧气和营养至关重要,同时在肿瘤病理的其他方面(如代谢失调和肿瘤扩散转移)也发挥关键作用。肿瘤内促血管生成因子和抗血管生成因子之间的不平衡会导致异常的血管网络建立,其特征是血管扩张不成熟、弯曲混乱和高渗透性,而异常的血管网络会引起肿瘤血流和氧合的时间和空间异质性及肿瘤间质液压力升高。这些异常及其形成的低氧微环境促进了肿瘤的生长和转移,导致化学疗法、放射疗法和免疫疗法的功效降低。为了对抗这种有缺陷的表型,肿瘤脉管系统正常化成为一种新的治疗策略[50]。通过血管正常化(即重建肿瘤血管结构和功能)恢复适当的肿瘤灌注和氧合作用,改善肿瘤微环境的代谢状况,可能会限制肿瘤细胞的侵袭性并提高抗癌治疗的有效性[50]。hAECs来源于胎盘,由于其端粒酶活性丧失,具有非致瘤性,同时也具有低免疫原性、多能干细胞的特征和调节血管形成的能力,因而被广泛用于组织工程学研究,以增加血液灌注并促进伤口愈合[3]。研究发现,将荧光标记hAECs经尾静脉注入到子宫内膜癌模型鼠中,hAECs归巢于子宫肿瘤组织,分化为肿瘤血管内皮细胞或血管外周细胞,整合到子宫内膜癌血管结构中,从而增强肿瘤血管的完整性和减少肿瘤血管生成失调,使得肿瘤血管的结构和功能正常化,提高了肿瘤血管灌注的效率,并增强了化疗药物顺铂的细胞毒性作用[51]。另外,hAECs对上皮性卵巢癌细胞(epithelial ovarian cancer,EOC)具有抑制作用。hAECs通过分泌TGF-β1介导癌细胞的细胞周期停滞在G0/G1期,从而发挥对EOC生长的抑制作用[52]。体内外研究表明,AM细胞可能通过抗增殖和促凋亡及调节血管生成和细胞周期等,来抑制肿瘤的生长和侵袭,从而发挥抗癌作用[53],加之hAECs在调节血管生成和诱导癌细胞凋亡方面起重要作用,其有望成为抗肿瘤治疗的候选者[54]。AM来源的hAECs不仅可用于再生医学,而且具有抗癌能力,hAECs及其衍生物为妇科恶性肿瘤的抗肿瘤治疗提供了新选择,但将其转化为临床应用仍需要进一步研究。

hAECs对复发性流产的免疫调节作用    复发性流产(recurrent spontaneous abortion,RSA)是育龄期女性的一种常见疾病,发病率为1%~5%。RSA的病因复杂,包括染色体异常、解剖结构异常、感染、内分泌因素和免疫性疾病等。然而,多达50%~75%的RSA病因不清楚,又称为原因不明的复发性流产(unexplained RSA,URSA)[55]。胚胎成功植入和妊娠维持需要母体对胎儿产生免疫耐受,但在保证妊娠期间胎儿免受母体免疫系统攻击的同时也要保证对病原体产生防御功能,因此母胎界面正常免疫稳态的建立对顺利妊娠至关重要[15]。辅助性T(T helper,Th)细胞及其相关细胞因子在母胎免疫调节中起重要作用,Th细胞被抗原呈递细胞激活后,开始克隆扩增和亚群分化(包括Th1细胞、Th2细胞、Th17细胞和Treg细胞等),同时分泌细胞因子并形成各自的细胞因子谱,从而决定随后的免疫应答类型,而母胎界面的Treg细胞减少和Th17/Treg比值升高可能会令母体形成不适当的胎儿免疫耐受,导致URSA的发生[56]。细胞因子在母胎之间的信号转导中也起重要作用:Th1细胞通常分泌促炎性细胞因子(如IFN-γ、TNF-α和IL-2),起到抑制胚胎植入和诱导流产的作用,同时Th2细胞可以分泌抗炎细胞因子(如IL-4、IL-6和IL-10),通过免疫抑制作用对同种异体反应产生免疫耐受性,有助于维持妊娠,外源性或内源性因素引起的Th1/Th2比例失衡会破坏母胎界面免疫耐受,从而导致妊娠终止[57]。hAECs位于与羊水接触的胎盘最内层,不仅具有多能干细胞的特性,而且通过发挥免疫调节作用来参与胎儿耐受性的维持[3]。hAECs对被刺激的T细胞的激活、增殖和促炎因子(IFN-γ和TNF-α)的产生都有明显的抑制作用[18],且hAECs来源的外泌体可通过旁分泌方式介导母胎之间的信号转导,发挥免疫调节作用并参与分娩启动[58]。研究表明,hAECs对URSA患者的幼稚Th细胞具有强大的免疫调节作用,包括抑制Th细胞增殖,促进Th细胞向亚群Treg细胞分化,使细胞因子谱偏向Th2模式以及抑制Th1和Th17细胞因子产生[59]。也有研究表明,hAECs降低了从URSA患者体内分离出的幼稚CD4+ T细胞活化的能力[60]。T细胞活化后TGF-β1表达上调,并在活化T细胞的增殖和分化中发挥关键作用[61],但hAECs会使活化T细胞的TGF-β1表达显著降低,将hAECs与幼稚T细胞共培养后,取上清,观察到TGF-β1水平降低[60]。另外,hAECs不表达HLA Ⅱ和共刺激分子[18],从而降低了临床应用后的免疫排斥风险,并且hAECs较容易大量地分离出来,同时不受道德伦理的约束。hAECs是调节母体免疫学异常的干细胞来源,对于RSA患者,hAECs可能是调节细胞介导的免疫异常的候选治疗药物之一。

结语    目前干细胞治疗仍然有许多有待解决的问题,包括治疗效果评估、治疗稳定性、致癌性、免疫应答、细胞来源和伦理学等方面[1]。胎盘通常在分娩后作为医疗废物被丢弃,且胎盘的获取无需其他任何侵入性操作,因此不会引起其他干细胞来源方面固有的伦理问题。一张AM可分离获得约2亿个hAECs,可制备足够数量的hAECs用于疾病治疗[3]。hAECs是尚未获得与年龄或环境相关的DNA损伤的新生细胞,免疫原性低[9]。hAECs具有遗传稳定性,移植到免疫缺陷小鼠体内不会形成肿瘤[22]。与其他干细胞相比,hAECs具有明显优势,是干细胞治疗的理想种子细胞。在妇产科领域,hAECs已被用于卵巢功能修复治疗、子宫内膜损伤修复治疗、剖宫产憩室修复治疗、妇科恶性肿瘤抗肿瘤治疗、复发性流产免疫调节治疗等研究中,具有广阔的应用前景。但真正应用于临床,仍需要进行多中心、大规模、前瞻性的临床研究评估,从而为今后hAECs在妇产科相关疾病治疗中的临床应用提供理论依据。

作者贡献声明  王璐璐  文献调研,论文构思、撰写和修订。赖东梅  文献调研,监督指导,论文修订和终审。

利益冲突声明  所有作者均声明不存在利益冲突。

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文章信息

王璐璐, 赖东梅
WANG Lu-lu, LAI Dong-mei
人羊膜上皮细胞在妇产科相关疾病中的应用及研究进展
Research progress and application of human amniotic epithelial cells in obstetrical and gynecological diseases
复旦学报医学版, 2021, 48(6): 819-826.
Fudan University Journal of Medical Sciences, 2021, 48(6): 819-826.
Corresponding author
LAI Dong-mei, E-mail:laidongmei@hotmail.com.
基金项目
国家重点研发计划(2018YFC1004802);国家自然科学基金(81971334)
Foundation item
This work was supported by the National Key R & D Program of China (2018YFC1004802) and the National Natural Science Foundation of China (81971334)

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