Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (7): 1081-1087.doi: 10.3969/j.issn.2095-4344.2176
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Wang Xianyao1, 2, Guan Yalin3, Liu Zhongshan3
Received:
2020-04-18
Revised:
2020-04-22
Accepted:
2020-05-19
Online:
2021-03-08
Published:
2020-12-09
Contact:
Liu Zhongshan, MD, Associate chief physician, Master’s supervisor, Department of Burn and Plastic Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
About author:
Wang Xianyao, Doctoral candidate, Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang 550004, Guizhou Province, China; Department of Immunology, Guizhou Medical University, Gui’an New Area 550025, Guizhou Province, China
Supported by:
CLC Number:
Wang Xianyao, Guan Yalin, Liu Zhongshan. Strategies for improving the therapeutic efficacy of mesenchymal stem cells in the treatment of nonhealing wounds[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(7): 1081-1087.
2.1 难愈性创面形成机制 创面愈合是一个完整、复杂的动态生物学过程,其可分为炎症反应期、组织增殖期和组织重塑期3个阶段,当某一阶段失控则会导致组织损伤无法得到正常的修复,形成难愈性创面。难愈性创面多是在各种潜在性疾病的基础上形成的,例如糖尿病、血管功能不全、烧伤、血管炎及辐射等[4]。事实上,创面的愈合过程往往会受到各种因素的干扰,主要包括感染、组织缺氧、坏死、渗出物和过量的炎性细胞因子等[5]。创面持续的炎症状态会产生级联反应,并使不愈合的状态持续下去。中性粒细胞过度浸润是慢性伤口的生物学标志,从一方面而言,中性粒细胞释放大量的酶,如胶原酶,分解细胞外基质影响细胞支架的形成;此外,中性粒细胞释放弹性蛋白酶,它会破坏部分细胞因子从而影响创面的愈合,如血小板衍生生长因子、转化生长因子β等[6]。目前临床对于难愈性创面的治疗手段仍为手术治疗,自体皮瓣移植是常用的手术方式。由于损伤部位和全身处于持续的炎症状态[7],为损伤修复带来了巨大的挑战。现阶段对于难愈性创面的治疗缺乏有效药物,而外科手术后伤口再上皮化过程也会受到一定的影响,因此针对难愈性创面的治疗迫切需要开发新的技术和治疗手段。 2.2 间充质干细胞治疗难愈性创面 间充质干细胞是一类具有自我更新能力的多能干细胞,在骨髓、脂肪组织、脐带、脐血、羊膜、牙髓等组织中均有发现,能够分化为成骨细胞、脂肪细胞和软骨细胞[8-9]。它们具有低免疫原性和免疫调节等优点,并且不同来源的间充质干细胞都具有诱导再生和维持组织内环境稳态的共同特征[10]。目前,虽然在临床和基础实验中间充质干细胞已经应用到多种疾病研究中,并显示出良好的治疗效果,但是大部分移植的间充质干细胞并不能充分发挥其治疗潜能,其主要原因包括迁移到损伤或病灶部位的干细胞数量有限,被局部微环境破坏,以及长时间的培养使其分化和增殖能力减弱等。因此,需要对间充质干细胞进行基因改造或预处理以增强细胞迁移或黏附能力,提高细胞对微环境的抵抗能力,提高细胞存活率和细胞抗衰老能力等。 2.2.1 间充质干细胞治疗难愈性创面的分子机制 早在2012年,BALAJI等[11]就总结了间充质干细胞修复创面的主要4种机制,即间充质干细胞直接分化为皮肤细胞参与创面修复、间充质干细胞免疫调节、间充质干细胞旁分泌效应促进血管化和再上皮化、间充质干细胞动员基底干细胞发挥创面修复作用。目前,间充质干细胞修复创面的分子机制也主要以间充质干细胞的多系分化机制,以及间充质干细胞通过旁分泌途径发挥免疫调节、促进创面血管化和再上皮化、动员基底干细胞发挥创面修复作用为主。 虽然间充质干细胞来源于中胚层,但已有大量报道支持间充质干细胞具备向其他胚层分化的潜能。间充质干细胞除了成骨、成脂、成软骨分化外,在一定条件下间充质干细胞还可分化为血管平滑肌细胞、角质形成细胞、肝细胞、胰岛细胞等其他细胞类型[12-14]。MAHMOOD等[15]从胎盘中分离出羊膜上皮细胞和间充质干细胞,经鉴定发现分别能分化成角质形成细胞和成纤维细胞,有利于严重烧伤的创面修复。此外,也有报道证实间充质干细胞可直接分化为表皮细胞、血管内皮细胞、结缔组织、成纤维细胞等直接参与创面的修复。例如,间充质干细胞可以直接分化为上皮组织参与组织的修复[16]。因此,间充质干细胞的分化特性使其成为未来开发人造皮肤的理想候选者,用于难愈性创面修复。 间充质干细胞具有强大的免疫调节能力,参与调节免疫细胞功能,利于创面修复。例如,将异体脂肪来源间充质干细胞应用于犬皮肤损伤,与常规治疗相比,脂肪来源间充质干细胞处理的伤口具有更高的再生能力,愈合速度更快;与对照创面相比,组织病理学检查显示炎性浸润消失,并出现多个毛囊,这表明脂肪来源间充质干细胞处理促进了表皮和真皮的再生[17]。此外,间充质干细胞可通过直接接触或分泌细胞因子的方式抑制包括巨噬细胞、自然杀伤细胞、树突状细胞、单核细胞等免疫细胞在内的先天免疫系统细胞的激活,也能在减少T细胞增殖的同时阻止细胞毒性T细胞的增殖和B淋巴细胞的分化[18]。NEMETH等[19]将脂多糖刺激的巨噬细胞与间充质干细胞共同培养时发现巨噬细胞产生更多的白细胞介素10,但如果间充质干细胞缺乏编码Toll样受体4、髓样分化因子MyD88、肿瘤坏死因子受体1α或环氧合酶2基因,这种现象就会消失。进一步研究发现间充质干细胞释放前列腺素E2,通过前列腺素EP2和EP4受体作用于巨噬细胞,从而影响细胞因子的分泌。然而,EL-SAYED等[20]将不同来源以及不同培养代次的间充质干细胞与脾脏来源单个核细胞培养,发现各种来源的间充质干细胞均可抑制CD4的表达,而骨髓来源间充质干细胞抑制CD8的表达,脂肪来源间充质干细胞上调CD8的表达。脂肪来源间充质干细胞除了能促进单个核细胞释放白细胞介素10外,还可促进白细胞介素6、转化生长因子β的释放。但是与培养代次较早的骨髓来源间充质干细胞(第1代)相比,培养代次较晚的骨髓来源间充质干细胞(第6代)释放的转化生长因子β较少。因此,细胞来源和质量决定着间充质干细胞的免疫调节特性,提高间充质干细胞的免疫调节特性也是促进间充质干细胞治疗难愈性创面的关键因素。 间充质干细胞可通过旁分泌作用分泌多种因子促进组织修复并营造适宜的微环境。在患有Ⅰ型白细胞黏附缺陷综合征(LAD1)的小鼠中,编码β2整合素共同β链的CD18基因突变会导致伤口愈合受损。通过移植间充质干细胞可恢复CD18基因突变的创面正常愈合速率,恢复转化生长因子β1水平。间充质干细胞释放的转化生长因子β1可促进肌成纤维细胞分化、伤口收缩和血管形成。JIANG等[21]发现这种调节依赖于转化生长因子β1受体的感知,并将信号传递到miR-21,而miR-21抑制转化生长因子β1信号的负调控因子Smad7的翻译。MYUNG等[22]检测发现富血小板血浆培养的脐血间充质干细胞分泌的细胞因子中血管内皮生长因子表达水平升高,体内实验发现脐血间充质干细胞联合富血小板血浆治疗组小鼠放射性皮肤溃疡伤口组织中血管内皮生长因子和CD31的表达较未治疗组增加,联合治疗可通过促进小鼠放射性皮肤溃疡模型中的血管生成来提高组织再生效率。最近研究表明,间充质干细胞来源的外泌体也在组织修复中发挥着重要作用。例如,经血间充质干细胞来源的外泌体可以通过诱导M1-M2巨噬细胞极化来降低炎症反应,上调血管内皮生长因子A促进新生血管生成[23]。体内实验也发现外泌体很可能通过NF-κB p65亚基的上调和激活NF-κB信号通路,加速小鼠的再上皮化。此外,间充质干细胞来源的外泌体可以通过促进胶原合成和血管生成,进而促进创面的修复[24]。因此,间充质干细胞来源的外泌体有效地提高了难愈性创面愈合效率,可用于再生医学,特别是难愈性创面的修复,如反射性皮肤溃疡、糖尿病足溃疡等。 间充质干细胞也可通过分泌细胞因子,动员基底干细胞参与创面修复。例如,间充质干细胞通过分泌细胞因子,激活β2肾上腺素能受体信号,促进角质形成细胞迁移,加速创面愈合[25]。HOSSEINZADEH等[26]将间充质干细胞与角质形成细胞在纳米纤维支架上共培养,发现间充质干细胞促进再上皮化过程,利于伤口愈合。此外,间充质干细胞也能促进成纤维细胞和角质形成细胞的迁移来促进创面愈合[27-28]。 2.2.2 通过基因修饰提高间充质干细胞治疗效果 应用间充质干细胞治疗难愈性创面时,通常都是以局部注射的方式进行给药。因此,通过对间充质干细胞进行基因修饰主要是为了提高细胞的黏附、增殖、存活能力以及减缓细胞衰老等。提高间充质干细胞的黏附性是决定其增殖和存活的关键,有助于细胞移植和组织再生。研究表明,细胞黏附能力与整合素关系密切,整合素通过黏附分子和细胞外基质参与调节细胞间黏附[29]。通过提高整合素和黏着斑复合物的表达可提高间充质干细胞的黏附能力。例如,将大鼠骨髓间充质干细胞高表达整合素连接激酶,细胞内ERK1/2和Akt的磷酸化水平增加,细胞存活率显著提高[30]。MAO等[31]首次在缺氧条件下高表达整合素连接激酶,发现骨髓间充质干细胞的白细胞介素6表达和分泌显著增加,骨髓间充质干细胞的自我更新能力和存活率得到提高。由于白细胞介素6的增加,检测到JAK2/STAT3信号激活,并显著上调lncRNA-TCF7的表达,促进了维持骨髓间充质干细胞活力和干性所需的Wnt/β-catenin 信号通路的激活。此外,WP1066特异性抑制STAT3信号转导和沉默lncRNA-TCF7的表达消除了整合素连接激酶过表达对低氧状态下骨髓间充质干细胞存活和自我更新的保护作用。总之,整合素连接激酶促进骨髓间充质干细胞存活和自我更新,提示高表达整合素连接激酶的骨髓间充质干细胞在组织修复领域具有较大的应用潜力。除了直接改变细胞黏附相关基因的表达外,也可以通过改变非编码RNA(ncRNA)来调控间充质干细胞黏附。例如,高表达miR-9-5p不仅可以增强大鼠骨髓间充质干细胞的迁移能力,而且改善了细胞黏附性[32]。miR-9-5p直接靶向CK1α和GSK3β,促进骨髓间充质干细胞中β-catenin入核,增加β-catenin 信号通路靶基因Runx2和c-Myc的表达,而且miR-9-5p-β-catenin信号轴涉及调控黏着斑的组装和细胞骨架的重排。移植的骨髓间充质干细胞对组织损伤修复效果不佳的原因主要是病灶组织血供不足、氧含量低。COPLAND等[33]研究了小鼠骨髓间充质干细胞对氧含量低、营养不良的应激环境的反应,以确定在骨髓间充质干细胞移植之前可以进行基因改造的目标分子。结合基因芯片和蛋白质组学筛选,他们发现纤溶酶原激活物抑制物1(PAI-1)是在体外模拟缺血条件下持续上调的分子,随后研究将纤溶酶原激活物抑制物1定义为骨髓间充质干细胞在体内存活的负调控因子。骨髓间充质干细胞来源的纤溶酶原激活物抑制物1并不通过纤溶酶依赖的方式影响间充质干细胞的存活,而是直接影响间充质干细胞与其周围基质的黏附性。因此,抑制或敲除纤溶酶原激活物抑制物1基因表达可增强间充质干细胞黏附和移植细胞存活率,促进治疗效果。 移植的间充质干细胞存活率往往受到低氧和低营养条件的限制,而提高移植间充质干细胞的存活率对于改善创面愈合的疗效也起着积极的作用。缺氧诱导因子1α是调节缺氧适应性反应的关键转录因子,缺氧诱导的细胞迁移、增殖、分化和血管生成过程均与Notch信号上游的缺氧诱导因子1α直接相关[34]。当改变大鼠骨髓间充质干细胞中缺氧诱导因子1α的表达,并将其暴露于缺氧低糖环境中,LV等[35]实验发现在缺氧低糖条件下高表达缺氧诱导因子1α可提高细胞存活率,减少G1期细胞积聚,抑制细胞凋亡。进一步研究发现,高表达缺氧诱导因子1α使Beclin1的表达增加,LC3 Ⅱ/LC3 Ⅰ 的比值降低,使PI3K/AKT/mTOR信号失活;而缺氧诱导因子1α下调可使PI3K/AKT/mTOR信号激活。因此,高表达缺氧诱导因子1α可通过细胞自噬和PI3K/AKT/mTOR信号通路参与保护骨髓间充质干细胞免受缺氧低糖环境诱导的损伤。肝细胞生长因子是另一种参与血管生成、抗炎以及抗凋亡的重要细胞因子。将人脐带间充质干细胞高表达肝细胞生长因子,发现缺氧条件下细胞凋亡率降低[36],缺氧条件下高表达肝细胞生长因子的人脐带间充质干细胞培养液中检查到更高水平的磷酸化Akt(p-Akt),降低Bax/Bcl-2比例。此外,缺氧条件下细胞培养液中血管内皮生长因子、表皮生长因子和碱性成纤维细胞生长因子的表达水平显著升高。因此,高表达肝细胞生长因子显著降低人脐带间充质干细胞移植凋亡率,促进细胞存活,有利于发挥组织修复的功能。DONG等[37]将大鼠骨髓间充质干细胞通过慢病毒的方式高表达miR-10a,发现miR-10a抑制KLF4-Bax/BCL2信号通路,降低了缺氧诱导的细胞凋亡,提高了成熟骨髓间充质干细胞的存活率。此外,也有其他修饰基因,包括高表达长链非编码RNA H19 (lncRNA H19)[38]、miR-21[39]、Gremlin1(GREM1)[40]、蛋白激酶C?[41]、脑源性神经营养因子受体(TrkB)[42]、肿瘤坏死因子受体(TNFR)[43],共同高表达Bcl-2和血管内皮生长因子[44],以及抑制miR-34a等[45]。 间充质干细胞基因修饰的另一个关键问题是减缓培养或移植的细胞衰老。细胞衰老是不可逆的细胞增殖停滞,也是间充质干细胞移植效果不佳的重要原因。高表达Sox2和Oct4基因已被证明能导致人脂肪间充质干细胞G1期细胞比例减少,S期细胞比例增加,说明Sox2和Oct4能使脂肪间充质干细胞从G1期向S期的转变加快,有效提高移植脂肪间充质干细胞的分化和增殖潜能[46]。LI等[47]将高表达Sox2和Oct4基因的脂肪间充质干细胞与巨噬细胞RAW264.7共培养,与对照组培养上清液相比,共培养上清液诱导的RAW264.7细胞的促炎细胞因子表达明显降低。体内实验显示与对照注射组相比,高表达Sox2和Oct4基因的脂肪间充质干细胞组小鼠疾病评分降低到34.9%,存活率提高了11.1%。因此,高表达Sox2和Oct4除了降低脂肪间充质干细胞衰老,促进细胞增殖与分化外,还能提高脂肪间充质干细胞的抗炎作用。此外,线粒体活性氧(mtROS)稳态的破坏是诱导间充质干细胞衰老的关键因素。因此,防止线粒体活性氧积累有助于抑制间充质干细胞衰老。JUNG等[48]观察到人脐血间充质干细胞以传代依赖的方式反向调节EphrinB2和EphB2的表达,EphB2信号诱导SIRT3线粒体易位。SIRT3基因敲除可抑制EphB2信号在人脐血间充质干细胞中的作用,EphrinB2-Fc通过c-Src磷酸化依赖的方式诱导NRF-2的核转位,而NRF-2调控SIRT3的表达。EphB2基因高表达使人脐血间充质干细胞中锰超氧化物歧化酶水平升高,线粒体活性氧水平降低。此外,SIRT3的脱乙酰酶作用通过赖氨酸68位点的脱乙酰基增强了锰超氧化物歧化酶的活性,EphB2的激活增强了人脐血间充质干细胞对皮肤创面愈合的治疗作用。因此,EphB2可通过EphB2/c-Src信号通路和NRF-2依赖的SIRT3表达,通过锰超氧化物歧化酶介导的线粒体活性氧清除作用,为提高人脐血间充质干细胞在创面修复治疗中的疗效提供新的靶点。 2.2.3 通过预处理提高间充质干细胞的治疗效果 间充质干细胞的预处理主要是利用化学或物理方式对间充质干细胞进行体外处理,以期维持和增强间充质干细胞黏附、增殖、存活能力,减少细胞衰老等。此外,预处理也可以改善间充质干细胞与先天/适应性免疫系统的相互作用。例如,经过低氧处理的间充质干细胞可通过释放多种抗炎细胞因子,尤其是白细胞介素10[49],使间充质干细胞比正常状态下具有更强的抗炎作用。JIANG等[50]发现低氧刺激可以增强人牙龈来源间充质干细胞对外周血单个核细胞的抑制作用,提高人牙龈来源间充质干细胞的免疫调节作用。体内实验表明,24 h低氧刺激可显著促进人牙龈来源间充质干细胞的皮肤创面修复能力。经过低氧处理的人牙龈来源间充质干细胞可以通过降低炎症细胞因子肿瘤坏死因子α、升高抗炎细胞因子白细胞介素10等来抑制损伤皮肤的局部炎症,提高创面修复疗效。 如前所述,纤溶酶原激活物抑制物1是纤溶酶原激活系统的关键调节因子,也是影响间充质干细胞移植后在病灶组织中存活的重要因素。既往研究表明,在纤溶酶原激活物抑制物1中和抗体存在的情况下,移植到损伤组织的细胞存活率显著增加,而且辛伐他汀在调节纤溶酶原激活物抑制物1水平的蛋白质级联反应中起着重要的作用。De FARIA等[51]将辛伐他汀作为间充质干细胞移植的佐剂,发现辛伐他汀促进间充质干细胞归巢效率,从而提高间充质干细胞对组织修复的疗效。促红细胞生成素主要由肾脏产生,能促进红系祖细胞的增殖和分化,因此,它被广泛应用于各种贫血的临床治疗,如再生障碍性贫血等[52]。研究发现,促红细胞生成素受体也广泛分布于除肾脏以外的各种系统,如大脑,因此,促红细胞生成素具有神经保护、抗氧化、抗炎、抗凋亡、抗氧化等功能[53]。此外,促红细胞生成素受体也分布在间充质干细胞中,LU等[54]在体外将人骨髓间充质干细胞以促红细胞生成素预处理,发现促红细胞生成素能在高糖微环境中刺激骨髓间充质干细胞分泌血管内皮生长因子。更重要的是,促红细胞生成素能减轻高糖微环境对骨髓间充质干细胞的损伤,并促进其增殖和迁移功能,抑制高糖诱导的骨髓间充质干细胞分泌炎症因子肿瘤坏死因子α。体内实验显示促红细胞生成素预处理的骨髓间充质干细胞实验组血管生成明显高于对照组,间充质干细胞部分分化为内皮细胞。此外,促红细胞生成素激活的骨髓间充质干细胞可抑制局部糖尿病足溃疡的单核细胞浸润。 在氧化应激条件下,间充质干细胞活性降低,并伴有凋亡发生。BAI等[55]用肿瘤坏死因子α预处理大鼠骨髓间充质干细胞24 h,发现骨髓间充质干细胞在氧化应激下的存活和迁移能力均增强。进一步研究发现肿瘤坏死因子α预处理可通过NF-κB信号途径促进骨髓间充质干细胞在氧化应激下的存活和迁移。缺氧预处理的间充质干细胞也可通过HIF-1α和Beclin-1信号通路发挥神经保护作用[56]。不同低氧浓度预处理可减缓人骨髓间充质干细胞衰老,在骨髓间充质干细胞的治疗中显示出良好的效果。例如,体积分数为1%O2可以促进骨髓间充质干细胞增殖、细胞存活、干细胞相关基因OCT4和趋化因子受体CXCR7的表达,降低衰老相关基因β-gal的表达[57]。此外,缺氧(体积分数为2% O2)预处理导致78 kD 葡萄糖调节蛋白(GRP78)的表达上调,HIF-1α-GRP78-Akt信号激活,使移植人脂肪间充质干细胞存活、增殖、迁移和血管生成因子分泌能力增强[58]。 HEO等[59]在分析多聚赖氨酸对人骨髓间充质干细胞基因表达谱的影响时发现,多聚赖氨酸上调参与细胞周期、黏附、干性维持、增殖、分化和FGF-2信号传导等基因表达,并且多聚赖氨酸能够促进骨髓间充质干细胞生长,减缓其衰老。多聚赖氨酸培养法为骨髓间充质干细胞生长提供了有利的微环境。此外,中药提取物也可用于间充质干细胞预处理,以促进细胞增殖,减少细胞凋亡,减缓细胞衰老。SANAP等[60] 首次发现中药提取物预处理人华通胶来源间充质干细胞后,细胞衰老延迟,凋亡细胞减少,增殖增加,细胞周期G2/M期增加。 预处理除了维持和增强间充质干细胞固有特性外,还能恢复间充质干细胞受损的功能。例如,胰岛素样生长因子1和成纤维细胞生长因子2联合预处理糖尿病小鼠骨髓间充质干细胞1 h,KHAN等[61]发现IGF-1、FGF-2、Akt、GATA-4、Nkx2.5等表达上调,而p16(INK4a)、p66(SHC)、p53、Bax、Bak等表达下调。在低氧应激条件下,胰岛素样生长因子1和成纤维细胞生长因子2联合预处理的骨髓间充质干细胞表现出较高的超氧化物歧化酶活性(52.3%),Annexin-V阳性细胞数降低,趋化迁移能力增强。此外,联合预处理后骨髓间充质干细胞的存活、增殖、促血管生成能力均得到改善,Akt磷酸化水平增加[62]。因此,联合应用胰岛素样生长因子1和成纤维细胞生长因子2预处理可能是一种增强恢复间充质干细胞受损功能,促进难愈性创面修复的新策略。 研究表明,血管紧张素Ⅱ预处理不仅增加间充质干细胞的自身保护作用,还可以加强间充质干细胞的旁分泌功能,加速创面愈合和组织修复。如宋奕辰等[63]发现血管紧张素Ⅱ预处理大鼠骨髓间充质干细胞能够通过Akt、ERK1/2 通路,明显减轻H2O2诱导的细胞损伤,显著提高骨髓间充质干细胞活力。杨靖等[64]以血管紧张素Ⅱ预处理脐血间充质干细胞后,发现脐血间充质干细胞上清液明显促进人脐静脉内皮细胞增殖、抑制细胞凋亡。创面早期的治疗关键之一是恢复血流和修复受损的内皮细胞,因此,将血管紧张素Ⅱ预处理的间充质干细胞应用于难愈性创面治疗具有较好的临床前景。"
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