Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (13): 2127-2132.doi: 10.12307/2022.344
Liu Ziwen, Wang Wenbo
Received:
2020-08-21
Revised:
2020-08-31
Accepted:
2020-10-09
Online:
2022-05-08
Published:
2021-12-20
Contact:
Wang Wenbo, MD, Chief physician, Professor, Doctoral supervisor, Third Department of Orthopedics, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
About author:
Liu Ziwen, Master candidate, Third Department of Orthopedics, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
CLC Number:
Liu Ziwen, Wang Wenbo. Regulatory effects of hypoxic culture on physiological activities of mesenchymal stem cells[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(13): 2127-2132.
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2.1.1 细胞增殖与迁移 间充质干细胞的增殖和迁移与骨骼健康发育和组织修复密切相关。近年来多位研究者利用不同氧体积分数处理间充质干细胞,结果表明缺氧培养可以调节间充质干细胞增殖能力。将间充质干细胞暴露于缺氧(体积分数为1% O2)和常氧(体积分数为21% O2)环境中,与常氧培养相比,在缺氧环境下培养7 d后人骨髓源性间充质干细胞和人脂肪源性间充质干细胞的细胞数量显著增加[13-14],且氧体积分数在1%-3%之间促进作用无明显差异[14]。此外,缺氧状态促使间充质干细胞形态变得小而圆,并趋向于增殖中心彼此覆盖,形成细胞克隆,在边缘产生大量增殖和扩散的子代细胞[15]。低氧诱导因子1α过表达也可以促进骨髓来源间充质干细胞增殖[16]。然而,小泛素样修饰剂连接酶的抑制剂没食子酸处理可以完全抵消由低氧诱导因子1α介导的间充质干细胞增殖,这意味着低氧诱导因子1α诱导的间充质干细胞增殖与小泛素样修饰剂途径有关[17-18]。值得注意的是,体积分数为1%O2缺氧环境比体积分数为5% O2缺氧环境培养的间充质干细胞具有更强的增殖能力[19]。 间充质干细胞具有向损伤组织迁移的能力,如缺血的大脑。骨髓间充质干细胞的迁移是由许多不同的趋化因子及其在骨髓间充质干细胞表面的受体介导的。来自局部或邻近干细胞巢中间充质干细胞的募集和迁移可以在损伤组织愈合中发挥修复作用[20-21]。氯化钴(CoCl2)是一种缺氧模拟剂,通过诱导低氧诱导因子1α和血管内皮生长因子的表达来模拟缺氧环境。越来越多的证据表明,含氧量为1%或由氯化钴诱导的低氧培养均对间充质干细胞迁移能力具有显著促进作用[22]。与常氧状态相比,缺氧状态的间充质干细胞对RhoA信号激活更为敏感,这有利于细胞迁移并促进间充质干细胞向伤口愈合方向迁移[23]。 近期研究表明,趋化因子基质细胞来源因子1(SDF-1)与其趋化因子受体C-X-C受体4型(CXCR4)或CXCR7之间的相互作用是干细胞趋化过程的关键调节器[24]。缺氧通过上调基质细胞来源因子1及其受体CXCR4和CXCR7的表达,从而提高间充质干细胞的有丝分裂能力[22]。此外,低氧诱导因子1α的过表达可以促进间充质干细胞募集,与缺氧培养作用相似[25]。 2.1.2 细胞自我更新和分化 骨组织的发育和再生是一个动态过程,主要包括骨形成和骨吸收。间充质干细胞的自我更新能力和多重分化之间的平衡是维持骨稳态的基础。间充质干细胞分化而来的成骨细胞通过合成和分泌骨基质、调节钙磷平衡参与骨形成过程,而间充质干细胞分化而来的成脂细胞将导致骨髓脂肪增加和骨质流失,阻碍骨的再生并引起骨质疏松。 Oct4和Nanog等多能性基因通过抑制分化相关基因表达来维持多能性,在自我更新过程中起着至关重要的作用。与常氧培养相比,缺氧条件下间充质干细胞干性基因Oct4和Nanog的表达水平均有所升高,从而促进间充质干细胞自我更新[15]。此外,缺氧刺激可显著增加白细胞介素6的分泌并激活STAT3信号传导,进而上调lncTCF7表达,诱导Wnt信号传导,促进间充质干细胞自我更新[26]。 尽管缺氧培养已被证明具有促进间充质干细胞自我更新的作用,但其在骨髓间充质干细胞分化中的作用仍存在争议。有研究表明,缺氧条件促进干性基因表达,使间充质干细胞保持在未分化状态,骨形成、脂肪形成和软骨形成均减少[27]。短暂缺氧培养(体积分数为2%O2)并进行成骨诱导7 d后,间充质干细胞中的成骨关键调控基因ALP及Runx2/Cbfa1的表达明显降低,成骨分化减弱,但是在培养28 d后Runx2/Cbfa1的表达与对照组相比无显著变化。此外,Notch1可以通过降低Runx2的表达和转录活性,在缺氧诱导间充质干细胞成骨抑制中发挥重要作用。另一方面,缺氧可以通过促进TWIST的表达从而抑制type 1 RUNX2启动子活性介导的间充质干细胞成骨分化信号通路[28]。全氟三丁胺是一种合成的氧气载体,可以通过抑制缺氧相关基因的表达促进成骨作用并促进骨骼形成,从而增加了间充质干细胞对周围氧的利用率[29]。同样,作为脂肪形成关键调控因子,过氧化物酶体增殖激活受体的mRNA转录水平在缺氧环境下会受到抑制,而未折叠蛋白反应激活抑制剂4-苯基丁酸可以逆转这一过程[30]。 但是也有一些学者报道了缺氧对间充质干细胞分化的积极作用。与常氧(体积分数为21%O2)相比,低氧预处理(体积分数为2% O2)后人脂肪间充质干细胞在分化培养基中培养22 d,其成脂和成骨分化潜能得到增强[31]。使用氯化钴模拟缺氧条件对间充质干细胞进行预处理后诱导成骨分化,与对照组相比,碱性磷酸酶、骨钙素和Ⅰ型胶原表达显著上调,导致矿化积累[32]。VALORANI等[33]也发现,尽管缺氧预培养抑制缺氧条件下的成脂分化,但是缺氧预培养后使间充质干细胞在常氧条件下具有更高的分化潜能。缺氧诱导Akt磷酸化能进一步介导低氧诱导因子1α表达,以促进软骨形成分化[34]。缺氧也可以逆转炎症因子白细胞介素1诱导的炎症反应对软骨分化的抑制[35]。此外,缺氧模拟剂氯化钴还可以增强聚集蛋白聚糖、sox9和Ⅱ型胶原蛋白的形成,以促进软骨细胞分化[32]。 然而也有一些研究表明,缺氧只影响间充质干细胞的增殖能力,不影响成骨、脂肪和软骨形成的分化能力[36]。此外,低氧诱导因子1α的过表达对细胞外钙沉积没有显著影响[16]。在骨发育和组织修复过程中,缺氧也可以调节间充质干细胞的分化能力,这种现象很可能是由于不同实验室、不同组织来源间充质干细胞、不同氧气体积分数和细胞培养时间的差异以及分化程度检测方法差异所致。因此,研究缺氧对间充质干细胞的作用时必须严格控制实验条件。 2.1.3 细胞凋亡 尽管短暂的低氧预处理对间充质干细胞活性是有利的,但是组织损伤处持续的低氧及缺血环境也是间充质干细胞移植治疗失败的主要原因。在间充质干细胞移植到缺损组织的最初24 h之内,大约99%的间充质干细胞会发生凋亡[37]。 细胞凋亡的主要信号传导途径有2种:死亡受体途径和线粒体途径。最近的一项研究表明,血清缺乏和缺氧诱导的间充质干细胞凋亡主要受到线粒体途径影响,而不受死亡受体途径的调控。小分子巨噬细胞迁移抑制因子(macrophage migration inhibitors,MIF)可以通过抑制基因间长链非编码(linc)RNA?p21来维持Wnt/β-catenin信号通路的激活,从而抑制Caspase家族活性和细胞凋亡,增强间充质干细胞的抗缺氧诱导细胞凋亡的能力[38]。此外,Ang1/Tie-2信号传导、C1q肿瘤坏死因子相关蛋白3(CTRP3)及硫化氢(H2S)联合内源性胱氨酸内溶酶(CSE)等均能通过其下游PI3K/Akt信使途径减少间充质干细胞移植治疗过程中低氧环境造成的细胞凋亡[39]。在模拟心肌缺血的低氧环境下,溶血磷脂酸(LPA)可以通过与ERK1/2和PI3K信号通路并行连接的Gi偶联LPA1受体来保护间充质干细胞线粒体的完整性和功能,从而抑制缺氧引起的细胞线粒体损伤[40]。 2.2 缺氧对间充质干细胞再生治疗的调控 "
由于间充质干细胞具有组织多源性、分化多能性、自我更新能力并能分泌与增殖和存活相关的细胞因子,具有免疫调节和潜在血管生成等优良特性,是组织再生的理想细胞来源[41- 42]。 此外,抗炎、免疫调节和免疫抑制等特性使间充质干细胞具有用于免疫耐受治疗的潜能。越来越多的证据表明基于间充质干细胞的再生疗法在多种体外动物疾病模型和多项临床试验中均能发挥良好的治疗作用。间充质干细胞在再生医学中的应用主要集中于骨骼[43]、心肌、神经系统[44]、肝脏、肾脏[45]、肺等相关的损伤组织重建[46]。由于缺氧对间充质干细胞活性及分化能力的多重影响,许多研究调查了缺氧与间充质干细胞之间的相互作用,并阐明了其作用机制。 2.2.1 骨缺损治疗 目前,间充质干细胞移植治疗软骨缺损和骨关节炎等多种骨病已取得一定的进展[46-47]。在临床治疗中,间充质干细胞已成功应用于骨缺损部位的骨重建[48]。多项环境因素均可以影响间充质干细胞的治疗效果,而缺氧是最重要的因素之一。普遍认为,健康骨骼中的氧体积分数在3%-8%之间,而在一些大骨损伤部位,随着营养利用率的降低,氧体积分数可能小于1%[49]。间充质干细胞移植至骨缺损部位后,因突然从正常培养环境进入缺氧环境,其局部氧微环境也由常氧(体积分数21% O2)变为缺氧[50],移植后很难存活,但是通过对移植前的间充质干细胞进行缺氧预处理,可以显著提高间充质干细胞的存活率[51],同时缺氧预处理可以通过诱导低氧诱导因子1α的表达及增强间充质干细胞旁分泌作用,提高间充质干细胞促进组织损伤部位血管生成的潜能和提高细胞存活率[52]。细胞聚集成球状体是抵抗移植后细胞快速死亡的另一种方法,缺氧预处理可以显著促进间充质干细胞球体形成,细胞球体不仅可以增强细胞活力,还可以促进血管新生并促进严重原位骨缺损的骨形成[50]。据报道旁分泌机制参与了间充质干细胞的移植调控,而外泌体是这种旁分泌作用的关键组成部分。与常氧条件下相比,缺氧条件下间充质干细胞的外泌体通过控制低氧诱导因子1α激活产生miR-126,可促进血管生成、细胞增殖和迁移,在骨折愈合方面具有更大的优势[52]。 2.2.2 心肌梗死治疗 尽管过去几十年来心力衰竭的临床治疗取得了巨大进步,但由心肌梗死引起的心力衰竭仍然是全世界发病率和死亡率较高的疾病之一[53]。近年来,间充质干细胞移植已成为心肌梗死临床治疗的一种全新方法,通过其多能分化潜能、促血管生成以及免疫调节特性来增强心脏再生能力,并通过缩小梗死面积和抑制左心室纤维化来改善心脏功能[54]。目前研究表明,影响间充质干细胞移植后促进心肌再生的主要障碍是受体部位细胞活性低,导致治疗效果不佳,而在移植前通过缺氧预处理可以提高间充质干细胞的治疗效果[54]。与正常状态相比,间充质干细胞用体积分数为0.5%O2处理24 h后,其核因子κB亚基P65、P50、促存活蛋白p105、抗凋亡蛋白Bcl-2和Bcl-xL显著上调,细胞存活率显著增加。同样,缺氧预处理可以进一步预防心肌梗死后移植到梗死周围区域的间充质干细胞的凋亡。研究表明,在缺氧条件下,间充质干细胞分泌的外泌体可通过miR-125b预防心肌梗死引发的细胞凋亡并促进心脏修复[55]。根据常氧和缺氧条件下间充质干细胞的整体基因表达差异图发现瘦素(leptin)是缺氧条件下最强的诱导基因[56]。瘦素信号传导是维持间充质干细胞活力的重要步骤,通过诱导CXCR4表达促进间充质干细胞的迁移[57]。此外,瘦素对于增强间充质干细胞在心肌梗死中的治疗效果有重要作用,包括血管密度增加、梗死面积缩小、长期收缩功能改善和心肌纤维化抑制[58]。 有趣的是,在心肌细胞缺氧或复氧条件下以及低氧诱导因子1α过表达的培养基中,间充质干细胞更倾向于心肌细胞分化[59]。 2.2.3 神经系统损伤 神经系统损伤分为中枢神经系统损伤和周围神经系统损伤。中枢神经系统损伤是不可逆的,其主要包括脊髓损伤、脑外伤和脑卒中[60]。周围神经系统损伤以严重创伤为主,其次是骨折和血管损伤。间充质干细胞移植在中枢神经系统损伤修复中的作用已被明确证实,它对神经系统疾病导致的严重创伤和持续缺血及中枢神经功能障碍具有一定的作用[42]。然而,退化的中枢神经系统损伤毒性环境以缺氧病理为特征,这可能对移植干细胞的存活有影响,但是缺氧条件可以与促红细胞生成素发挥协同作用,通过抑制促红细胞生成素受体的合成来促进神经元标记物(β-微管蛋白Ⅲ、胆碱乙酰转移酶、神经元核抗原、毒蕈碱受体)及其功能标记物(脑啡肽酶、天冬氨酸转运体)的表达。与此同时,缺氧会诱导人源间充质干细胞发生神经元样分化,并与促红细胞生成素一起阻断神经胶质样分化。此外,体外缺氧和体内脑缺血引起的神经元损伤,间充质干细胞可以通过分泌血管内皮生长因子和脑源性神经营养因子促进神经元生长。临床中通过移植间充质干细胞来治疗缺血性脑损伤,间充质干细胞在移植后的缺氧环境下分泌神经营养因子,促进神经干细胞的分化及神经细胞恢复,从而改善患者预后[61-62]。 2.2.4 肝脏损伤治疗 近年来,大量基础和临床研究表明,基于间充质干细胞的再生疗法具有免疫抑制和修复肝脏损伤的能力,因此在免疫介导的肝损伤中具有显著的优势[63]。间充质干细胞移植还可以通过抑制纤维化和促进肝再生来减少肝损伤[64]。高氧浓度可以通过产生活性氧而引起氧化应激,从而破坏DNA和蛋白质[65]。在体外,通过缺氧预处理可以抑制间充质干细胞内活性氧活性,抑制肿瘤坏死因子α表达并增强转化生长因子β1分泌,促进细胞内和细胞外胶原生成以及降低促凋亡mRNA表达,从而增强间充质干细胞对肝细胞的营养供给和抗凋亡作用[66]。在大鼠广泛肝切除模型中,缺氧预处理的间充质干细胞移植后通过上调肝细胞生长因子表达[64],可显著减轻肝损伤,促进肝存活和再生。 2.2.5 肾脏损伤治疗 肾脏损伤包括急性肾损伤和慢性肾病[41]。多项研究表明,间充质干细胞具有肾小管上皮分化潜能,可抑制过度炎症反应,有助于肌成纤维细胞池的形成[67],在肾损伤修复中有重要作用,并且具有较高的安全性。缺血再灌注损伤是急性肾损伤的主要原因之一。在氯化钴模拟的缺氧条件下预处理间充质干细胞,可以激活低氧诱导因子1α并上调其靶基因CXCR4,使细胞更有效地迁移到缺血再灌注损伤部位并维持更长的时间[68]。缺氧预处理也显著促进间充质干细胞分泌血管生成因子(血管内皮生长因子、碱性成纤维细胞生长因子、肝细胞生长因子),增强间充质干细胞在缺血再灌注损伤部位的超氧化物清除和血管生成能力,抑制间充质干细胞的凋亡[69]。 2.2.6 肺部疾病治疗 肺是呼吸系统的主要器官,肺疾病属于呼吸系统疾病,主要包括慢性阻塞性肺疾病、支气管肺发育不良、急性肺损伤、哮喘和肺癌。由于童年后肺再生受到很多限制,肺干细胞的表型畸变和稀疏是肺病理学的关键特征和肺损伤的主要驱动力,干细胞疗法已成为治疗肺损伤具有前景的方法[70]。最新研究表明,将缺氧预处理的间充质干细胞移植到博来霉素诱导的肺纤维化小鼠模型中,可通过下调炎性因子(白细胞介素6和白细胞介素1β)的表达、减少肺胶原沉积和纤维化相关基因的表达,以减弱博来霉素诱导的气道收缩并减少肺水肿和纤维化组织病理学改变[71]。此外,缺氧培养还能通过低氧诱导因子1α调节细胞增殖和抗氧化能力,增强间充质干细胞对辐射诱导的小鼠肺损伤的治疗作用[72]。"
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