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SCI.据/journal-id>

干细胞国际据/journal-title>

1687 - 9678据/issn> 1687 - 966 x据/issn>

Hindawi据/publisher-name>

10.1155 / 2020/8882549据/article-id> 8882549.据/article-id>

研究文章据/subject>

髓核细胞条件培养基在缺氧条件下促进间充质干细胞向髓核样细胞分化据/article-title>

https://orcid.org/0000-0002-6591-2890据/contrib-id> Sinkemani据/surname> Arjun据/given-names>

王据/surname> 冯据/given-names> 谢据/surname> Zhiyang据/given-names> 陈据/surname> 陆据/given-names> 张据/surname> 琮据/given-names>

https://orcid.org/0000-0003-1974-8193据/contrib-id> 吴据/surname> 仙桃据/given-names>

Faroni据/surname> 亚历山德罗据/given-names>

脊柱外科据/addr-line> 中大医院据/addr-line> 东南大学医学院据/addr-line> 丁家桥路位于鼓楼区丁家桥87 #据/addr-line> 210009年南京据/addr-line> 中国据/country> seu.edu.cn据/ext-link>

2020据/year>

23据/day> 12据/month> 2020据/year>

2020据/volume> 27据/day> 9.据/month> 2020据/year> 15据/day> 11据/month> 2020据/year> 3.据/day> 12据/month> 2020据/year> 23据/day> 12据/month> 2020据/year>

这是一篇在知识共享署名许可下发布的开放存取的文章，它允许在任何媒体上无限制地使用、传播和复制，只要原始作品被适当地引用。据/license-p>

下腰痛(LBP)是世界范围内一个主要的身体和社会经济挑战。髓核(NP)与椎间盘退变引起的腰椎间盘突出症(LBP)直接相关。IVD退行性变主要是由于在衰老和退行性变过程中，IVD内部发生结构和基质相关的变化引起的。间充质干细胞(Mesenchymal stem cells, MSCs)在特定的刺激条件下可分化为多种间充质细胞系。本研究旨在评估髓核细胞(NPC)条件培养基促进MSCs表达的有效性，并确认脊柱研究兴趣小组最近推荐的健康NP表型标记的表达。采用定量聚合酶链反应(qPCR)和蛋白质印迹(western blotting)研究常氧和缺氧条件下的表达。qPCR和western blotting结果显示，50%或100% NPC条件培养基处理的MSCs在缺氧条件下与正常缺氧条件下相比，NP标记表达显著上调。与对照组相比，在100% NPC条件培养基中上调最高(aggrecan，据inline-formula> P.据/mml:mi> 据据/mml:mo> 0．01据/mml:mn> ；brachyury,据inline-formula> P.据/mml:mi> 据据/mml:mo> ０．０５据/mml:mn> ；胶原蛋白II,据inline-formula> P.据/mml:mi> 据据/mml:mo> 0.001据/mml:mn> ；KRT8,据inline-formula> P.据/mml:mi> 据据/mml:mo> 0．01据/mml:mn> ；KRT19,据inline-formula> P.据/mml:mi> 据据/mml:mo> 0.001据/mml:mn> ；嘘,据inline-formula> P.据/mml:mi> 据据/mml:mo> 0．01据/mml:mn> )．用50％NPC条件培养基处理的MSCs中基因的表达水平也显示出与对照组相比的上调（胶原II，据inline-formula> P.据/mml:mi> 据据/mml:mo> ０．０５据/mml:mn> ；KRT8,据inline-formula> P.据/mml:mi> 据据/mml:mo> ０．０５据/mml:mn> ；KRT19,据inline-formula> P.据/mml:mi> 据据/mml:mo> 0．01据/mml:mn> )．这些结果表明，NPC条件培养基刺激间充质干细胞分化为具有明显特征的np样表型。结果可为IVD再生策略提供参考。据/p> 国家自然科学基金项目据/funding-source> 81572170据/award-id> 81572190据/award-id> 81702190据/award-id> 81702203.据/award-id> 81702201.据/award-id> 江苏省中央大学和研究生研究与实践创新计划的基础研究资金据/funding-source> KYLX16_0302据/award-id> KYCX17_0182据/award-id> 2242016 k40149据/award-id> 2242017 k3dn06据/award-id> 江苏省卫生和计划生育委员会据/funding-source> H201533据/award-id> 1.介绍据/title> <p>下腰痛(LBP)是全世界致残的主要原因[据xref ref-type="bibr" rid="B1"> 1据/xref>，超过84%的人在一生中至少会受到一次影响[据xref ref-type="bibr" rid="B2"> 2据/xref>］.虽然可能是多因素，但LBP的潜在病因未知。椎间盘（IVD）变性是主要的临床介绍。椎间盘退化的主要原因是组织分解，主要是由于衰老，饮食差，遗传遗传或伤害[据xref ref-type="bibr" rid="B3"> 3.据/xref>］.IVD退化是一种过程，通常是由于IVD内的生物力学变化引起的。IVD退化的原因尚未完全阐明，但被推测包括环境和遗传因素[据xref ref-type="bibr" rid="B4"> 4.据/xref>］.椎间盘退变过程中，常驻细胞发生各种稳态改变，导致降解的组织合成代谢和升高的组织分解代谢[据xref ref-type="bibr" rid="B5"> 5.据/xref>］.椎间盘退变可由椎间盘组织脱水、蛋白多糖丢失、纤维化组织形成和椎间盘高度降低引起[据xref ref-type="bibr" rid="B3"> 3.据/xref>那据xref ref-type="bibr" rid="B6"> 6.据/xref>］.胶质细胞外基质分解，导致纤维组织形成，使髓核细胞(NPCs)应变[据xref ref-type="bibr" rid="B7"> 7.据/xref>那据xref ref-type="bibr" rid="B8"> 8.据/xref>］.据/p> <p>目前的治疗策略提供症状性疼痛缓解，而不是解决IVD退行性病变的潜在病因。脊柱融合术和椎间盘切除术是目前应用最广泛的腰椎间盘突出症手术治疗方法。在这些手术中，退变或突出的椎间盘被去除，附近的椎间盘用金属棒和骨水泥融合;后者用于椎体成形术和球囊后凸成形术[据xref ref-type="bibr" rid="B9"> 9.据/xref>那据xref ref-type="bibr" rid="B10"> 10据/xref>］.虽然手术的目的是缓解疼痛，但患者最终会经历持续的疼痛和脊柱活动减少[据xref ref-type="bibr" rid="B11"> 11据/xref>］.由于生物力学变化，这些手术可能会加速某些IVD节段的退行性变[据xref ref-type="bibr" rid="B12"> 12据/xref>那据xref ref-type="bibr" rid="B13"> 13据/xref>］.由于目前治疗的远期疗效较差，IVD退行性变的患病率越来越高，需要解决IVD退行性变的潜在发病机制，恢复正常的IVD功能，而不是简单地达到减轻疼痛的目的。因此，生物和细胞为基础的治疗是必要的替代治疗IVD退行性变。据/p> <p>基于细胞的治疗包括在退变椎间盘植入自体npc或干细胞，目的是通过在IVD退变早期替换npc来恢复IVD代谢稳态并减少炎症。间充质干细胞(Mesenchymal stem cells, MSCs)是细胞治疗的重要选择。MSCs是最常被研究和广泛应用于再生目的的细胞[据xref ref-type="bibr" rid="B14"> 14据/xref>］.研究表明，MSCs可分化为np样细胞，可能为IVD再生提供良好的细胞来源。此外，有研究表明MSCs与NPC条件培养基共培养可分化为np样细胞，并获得与NPC相似的表型[据xref ref-type="bibr" rid="B15"> 15据/xref>］.此外，在脊索细胞条件培养基中培养的MSCs在IVD内合成高水平的蛋白多糖，可能是通过代谢物、生长因子和细胞外基质蛋白刺激NPCs [据xref ref-type="bibr" rid="B16"> 16据/xref>-据xref ref-type="bibr" rid="B18"> 18据/xref>］.因此，MSCs具有较高的IVD再生能力[据xref ref-type="bibr" rid="B19"> 19据/xref>］.据/p> <p>骨科研究协会脊柱研究兴趣小组表示HIF-1稳定表达据italic> α据/italic>、glut1、骨胶蛋白/胶原蛋白II (据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"> <mml:mtext> 比据/mml:mtext> <mml:mo> >据/mml:mo> <mml:mn> 20.据/mml:mn> </mml:math> </inline-formula>)、Shh、brachyury、KRT18/19、CA12和CD24对脊柱健康是必要的[据xref ref-type="bibr" rid="B20"> 20.据/xref>］.然而，需要在基因和蛋白质水平进一步研究，以更好地了解MSC向np样细胞的分化。因此，本研究的目的是确定鼻咽癌条件培养基对常氧和缺氧条件下培养的MSCs表达的影响。采用定量聚合酶链反应(qPCR)和蛋白质印迹(western blotting)检测mRNA和蛋白水平，以探索可能促进间充质干细胞分化为np样细胞的基因和蛋白表达的变化，从而帮助治疗IVD变性。据/p> </sec> <sec id="sec2"> <title>2.材料和方法据/title> <sec id="sec2.1"> <title>2．1.npc的隔离和文化据/title> <p>东南大学动物保护与使用委员会批准了本研究中所有的动物实验。20只雄性sd大鼠(8周龄，200 ~ 300 g)行CO安乐死据sub>2据/sub>．如我们之前的研究所述，分离出NP组织[据xref ref-type="bibr" rid="B21"> 21据/xref>］.NPCs在含10%胎牛血清的Dulbecco’s modified Eagle’s培养基(DMEM)/F-12中培养;Gibco, Grand Island, NY, USA)和5% CO下1%青霉素-链霉素溶液据sub>2据/sub>和21%啊据sub>2据/sub>在37°C。使用0.25%胰酶- edta (1 mM)溶液(Life Technologies, Carlsbad, CA, USA)收获细胞并进行传代(1:2);在第1-3代收集细胞。每隔3天更换一次培养基。实验使用NPC条件培养基(第3段)。据/p> </sec> <sec id="sec2.2"> <title>2.2。MSC培养在50％或100％NPC条件培养基中据/title> <p>Sprague-Dawley大鼠骨髓间充质干细胞购自Cyagen Biosciences(中国苏州)。MSCs在含10%胎牛血清(Gibco)和1%青霉素-链霉素溶液的DMEM/F-12培养液中培养。所有细胞均在5% CO下培养据sub>2据/sub>和21%啊据sub>2据/sub>在37°C。每隔3天更换一次培养基。我们的研究使用了第5代的细胞。实验组MSCs在50%或100% NPC条件培养基中培养7 d，对照组MSCs在含10%胎牛血清(Gibco)和1%青霉素-链霉素溶液的DMEM/F-12培养液中培养。对照组培养基和实验组条件培养基每周更换2次。据/p> </sec> <sec id="sec2.3"> <title>２.３.缺氧条件下的细胞培养据/title> <p>npc在缺氧环境中培养(3131培养箱;Thermo Fisher Scientific, Waltham, MA, USA)在93%氮的条件下据sub>2据/sub>, 5%的公司据sub>2据/sub>，2％o据sub>2据/sub>在37°C (据xref ref-type="bibr" rid="B22"> 22据/xref>］.NPCs在添加10%胎牛血清和1%青霉素-链霉素溶液的新鲜DMEM/F-12中培养，缺氧3 d。如上所述，实验中使用了NPC条件培养基(第3段)。MSCs也在缺氧环境中培养(3131培养箱;在93%氮的条件下据sub>2据/sub>, 5%的公司据sub>2据/sub>，2％o据sub>2据/sub>在37°C (据xref ref-type="bibr" rid="B22"> 22据/xref>］.实验组MSCs在50%或100% NPC条件培养基中培养7 d，对照组MSCs在含10%胎牛血清(Gibco)和1%青霉素-链霉素溶液的DMEM/F-12培养液中培养。对照组培养基和实验组条件培养基每周更换2次。据/p> </sec> <sec id="sec2.4"> <title>2.4。定量聚合酶链反应据/title> <p>NPCs和MSCs分别在缺氧和常氧条件下培养于6cm板，分别在第3天和第7天提取总mRNA。使用通用RNA提取试剂盒(9767;豆类、大连、中国)。逆转录使用PrimeScript RT Reagent Kit with gDNA Eraser (RR047;根据制造商的说明)。qPCR采用SYBR Green PCR Master Mix(罗氏应用科学公司，Penzberg，德国)在StepOnePlus PCR系统(Applied Biosystems公司，Foster City, CA, USA)中进行分析。qPCR检测混合物含有0.5据italic> μ据/italic>L反向底漆（10 据italic> μ据/italic>m），2 据italic> μ据/italic>L的cDNA模板，0.5据italic> μ据/italic>L正向引物(10据italic> μ据/italic>米),10据italic> μ据/italic>L (SYBR Green溶液)，7据italic> μ据/italic>我的dh据sub>2据/sub>O.基因特异性引物序列见表据xref rid="tab1" ref-type="table"> 1据/xref>．目的基因表达水平归一化为据italic> β据/italic>-actin使用2据sup>-据italic> ΔΔ据/italic>CT.据/sup>循环阈值方法。据/p> <table-wrap id="tab1"> <label>表1据/label> <p>用于qPCR基因表达分析的引物序列。据/p> <table> <thead> <tr> <th align="left">基因据/th> <th align="center">向前（5.据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> '据/mml:mo> </mml:mrow> </mml:msup> </mml:math> </inline-formula>3据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M12"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> '据/mml:mo> </mml:mrow> </mml:msup> </mml:math> </inline-formula>）据/th> <th align="center">反向(5据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M13"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> '据/mml:mo> </mml:mrow> </mml:msup> </mml:math> </inline-formula>3据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M14"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> '据/mml:mo> </mml:mrow> </mml:msup> </mml:math> </inline-formula>）据/th> </tr> </thead> <tbody> <tr> <td align="left">HIF-1据italic> α据/italic></td> <td align="center">GCAACTGCCACCACTGATGA据/td> <td align="center">GCTGTCCGACTGTGAGTACC据/td> </tr> <tr> <td align="left">HIF-2据italic> α据/italic></td> <td align="center">GCACCAGCAGTTCACACTTG据/td> <td align="center">CTGACGGTCTTGTCAGGCAT据/td> </tr> <tr> <td align="left">凝灰套1据/td> <td align="center">GCTGTGGCTGGCTTCTCTAA据/td> <td align="center">CCGGAAGCGATCTCATCGAA据/td> </tr> <tr> <td align="left">嘘据/td> <td align="center">TATGAGGGTCGAGCAGTGGA据/td> <td align="center">AGTGGATGCGAGCTTTGGAT据/td> </tr> <tr> <td align="left">Brachyury据/td> <td align="center">TCTAGGCACAACATGGCAGG据/td> <td align="center">AAATTGGACCACAGCCTCGT据/td> </tr> <tr> <td align="left">Aggrecan据/td> <td align="center">TGGCCTGCCTGACTTTAGTG据/td> <td align="center">cctgaAccactgacgctgat.据/td> </tr> <tr> <td align="left">胶原二据/td> <td align="center">GGCCAGGATGCCCGAAAATTA据/td> <td align="center">ACCCCTCTCTCCCTTGTCAC据/td> </tr> <tr> <td align="left">碳酸酐酶3据/td> <td align="center">tggttcactggaacccgaag.据/td> <td align="center">GAGCCTCCTTGCCCTTAGTC据/td> </tr> <tr> <td align="left">碳酸酐酶12据/td> <td align="center">TCCGACAAGGACTGCTTTC.据/td> <td align="center">GGAGATCCCAAGGACACCAG据/td> </tr> <tr> <td align="left">CD24据/td> <td align="center">AGTAATTGACACGGGCCAGG据/td> <td align="center">tgggaaatgctttgccgttg.据/td> </tr> <tr> <td align="left">细胞角蛋白8据/td> <td align="center">CCCGGCTTCAGCTATGGAAT据/td> <td align="center">AGCCTTGGTGCGGCTATAAG据/td> </tr> <tr> <td align="left">细胞角蛋白18据/td> <td align="center">gacccaggaatacgaagccc.据/td> <td align="center">CATTTTGCCATCCACGACCTT.据/td> </tr> <tr> <td align="left">细胞角蛋白19据/td> <td align="center">GAGATCGCCACCTACCGAAG据/td> <td align="center">GGAAGGGCTGGTGTGAACTT据/td> </tr> </tbody> </table> <table-wrap-foot> <fn> <p>qPCR:定量聚合酶链反应。据/p> </fn> </table-wrap-foot> </table-wrap> </sec> <sec id="sec2.5"> <title>2．5．蛋白质提取和Western Blotting据/title> <p>在常氧和缺氧条件下培养的npc和MSCs分别放在冰上，收获，并在第3天和第7天用冷磷酸盐缓冲盐水(PBS)溶液清洗。用全细胞裂解试验缓冲液(KeyGen，中国南京)提取总蛋白。蛋白质浓度的测定采用双氰菊酯酸法(Beyotime，中国，江苏)。蛋白通过10% SDS-PAGE分离，转移到聚偏二氟乙烯膜上(EMD Millipore, Burlington, MA, USA)。用5%牛血清白蛋白(BSA)封闭细胞膜1.5小时，然后用一抗孵育过夜(见表)据xref rid="tab2" ref-type="table"> 2据/xref>)，在4°C轻微摇晃。随后，用二抗(ab6721, 1: 5000;Abcam, Cambridge, UK)，用5%牛血清白蛋白(BSA)在室温下稀释1小时。免疫标记使用SuperSignal West FEMTO化学发光衬底(Thermo Fisher Scientific)进行检测。用定量密度分析法测定相对蛋白表达水平，归一化至据italic> β据/italic>肌动蛋白。据/p> <table-wrap id="tab2"> <label>表2据/label> <p>用于WB和IF的抗体。据/p> <table> <thead> <tr> <th align="left">目标据/th> <th align="center">抗体（公司，订单号）据/th> <th align="center">世行的使用据/th> <th align="center">如果使用据/th> </tr> </thead> <tbody> <tr> <td align="left">HIF-1据italic> α据/italic></td> <td align="center">ABCAM，AB2185据/td> <td align="center">1：1000据/td> <td align="center">1：1000据/td> </tr> <tr> <td align="left">HIF-2据italic> α据/italic></td> <td align="center">Abcam, ab199据/td> <td align="center">1：1000据/td> <td align="center">1：1000据/td> </tr> <tr> <td align="left">凝灰套1据/td> <td align="center">Abcam, ab15309据/td> <td align="center">1: 250据/td> <td align="center">1: 250据/td> </tr> <tr> <td align="left">嘘据/td> <td align="center">Abcam, ab19897据/td> <td align="center">1: 250据/td> <td align="center">1：50据/td> </tr> <tr> <td align="left">Brachyury据/td> <td align="center">BIOSS，BS-10669R据/td> <td align="center">1: 250据/td> <td align="center">1: 250据/td> </tr> <tr> <td align="left">Aggrecan据/td> <td align="center">bios, bs - 11655 r据/td> <td align="center">1: 250据/td> <td align="center">1: 250据/td> </tr> <tr> <td align="left">胶原二据/td> <td align="center">Abcam, ab116242据/td> <td align="center">1：1000据/td> <td align="center">1：1000据/td> </tr> <tr> <td align="left">碳酸酐酶3据/td> <td align="center">Abcam, ab196835据/td> <td align="center">1：1000据/td> <td align="center">1: 100据/td> </tr> <tr> <td align="left">碳酸酐酶12据/td> <td align="center">春秋国旅(D78E4), 5865年据/td> <td align="center">1：1000据/td> <td></td> </tr> <tr> <td align="left">碳酸酐酶12据/td> <td align="center">bios, bs - 6025 r据/td> <td></td> <td align="center">1: 250据/td> </tr> <tr> <td align="left">CD24据/td> <td align="center">Proteintech, 10600 - 1 - ap据/td> <td align="center">1：1000据/td> <td></td> </tr> <tr> <td align="left">CD24据/td> <td align="center">bios, bs - 4891 r据/td> <td></td> <td align="center">1: 250据/td> </tr> <tr> <td align="left">细胞角蛋白8据/td> <td align="center">Abcam, ab59400据/td> <td align="center">1：1000据/td> <td align="center">1: 500据/td> </tr> <tr> <td align="left">细胞角蛋白18据/td> <td align="center">Abcam, ab181597据/td> <td align="center">1：1000据/td> <td align="center">1: 100据/td> </tr> <tr> <td align="left">细胞角蛋白19据/td> <td align="center">Abcam, ab84632据/td> <td align="center">1: 500据/td> <td align="center">1: 500据/td> </tr> <tr> <td align="left"> <italic> β据/italic>肌动蛋白据/td> <td align="center">ABCAM，AB8227据/td> <td align="center">1: 2000据/td> <td></td> </tr> </tbody> </table> <table-wrap-foot> <fn> <p>WB:免疫印迹;如果:免疫荧光。据/p> </fn> </table-wrap-foot> </table-wrap> </sec> <sec id="sec2.6"> <title>2.6。免疫荧光染色显微镜据/title> <p>将NPC在12孔板中涂覆，并在缺氧和常氧条件下保持3天。然后用4％多聚甲醛固定细胞20分钟。在玻璃底部载玻片（Cellvis，山景，CA，USA）上的NPC在含有5％BSA和PBS中的0.1％Triton X-100的缓冲液中封闭20分钟。然后，将NPC洗涤三次并用一抗抗体在4℃下温育过夜（表据xref rid="tab2" ref-type="table"> 2据/xref>)．细胞洗涤后，用二抗(Alexa Fluor 594山羊抗兔，1:10 00;Invitrogen公司，Carlsbad, CA, USA)室温下1小时。用4,6-二氨基-2-苯基吲哚(DAPI;Sigma-Aldrich, St. Louis, MO, USA)在室温下放置15分钟，并使用荧光显微镜观察(Olympus，东京，日本)。据/p> </sec> <sec id="sec2.7"> <title>2.7。统计分析据/title> <p>结果表示为据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M15"> <mml:mtext> 意味着据/mml:mtext> <mml:mo> ±据/mml:mo> <mml:mtext> 标准据/mml:mtext> <mml:mtext> </mml:mtext> <mml:mtext> 偏差据/mml:mtext> </mml:math> </inline-formula>来自三个独立实验。使用RappPad Prism软件（Ver。7.04; GraphPad Software，Inc.，La Jolla，CA，USA）进行统计分析，并使用未配对的学生分析团体之间的差异据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M16"> <mml:mi> T.据/mml:mi> </mml:math> </inline-formula>- 最低。差异据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M17"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>被认为是统计学意义的。据/p> </sec> </sec> <sec id="sec3"> <title>3.结果据/title> <sec id="sec3.1"> <title>3．1.常氧和缺氧条件下培养npc的基因表达据/title> <p>采用qPCR方法检测常氧和缺氧条件下Sprague-Dawley大鼠NPCs的基因表达。结果表明，推荐的健康青年鼻咽癌表型标记在常氧和缺氧条件下均有表达。NPCs的基因表达通常在缺氧条件下显著高于在常氧条件下，尽管HIF-2据italic> α据/italic>在常氧条件下表现出更高的表达(据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M18"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>)．CA3基因的表达水平低于KRT19、Shh、aggrecan、brachyury、collagen II和HIF-1据italic> α据/italic>在缺氧条件下(据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M19"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>）（数字据xref rid="fig1" ref-type="fig"> 1据/xref>)．相比之下，CA12、CD24、Glut-1、KRT8和KRT18在缺氧条件下表达显著升高(据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M20"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>）（数字据xref rid="fig1" ref-type="fig"> 1据/xref>)．据/p> <fig-group id="fig1"> <label>图1据/label> <p>标记推荐用于定义年轻健康的NP表型。QPCR在常氧和缺氧条件下培养的NPC中的相对基因表达。每种样品的基因表达水平被标准化为管家基因据italic> β据/italic>肌动蛋白。（a）藻康，（b）Brachyury，（c）碳酸酐酶3，（d）碳酸酐酶12，（e）CD24，（f）胶原II，（g）凝乳-1，（h）HIF-1据italic> α据/italic>，（i）HIF-2据italic> α据/italic>，（j）Krt8，（k）krt18，（l）krt19和（m）shh。据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M21"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>那据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M22"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>那据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M23"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.001据/mml:mn> </mml:math> </inline-formula>,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M24"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>．据/p> <fig id="fig1a"> <label>(一)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001a"></graphic> </fig> <fig id="fig1b"> <label>(b)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001b"></graphic> </fig> <fig id="fig1c"> <label>(c)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001c"></graphic> </fig> <fig id="fig1d"> <label>(d)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001d"></graphic> </fig> <fig id="fig1e"> <label>(e)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001e"></graphic> </fig> <fig id="fig1f"> <label>(f)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001f"></graphic> </fig> <fig id="fig1g"> <label>(g)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001g"></graphic> </fig> <fig id="fig1h"> <label>(h)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001h"></graphic> </fig> <fig id="fig1i"> <label>(我)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001i"></graphic> </fig> <fig id="fig1j"> <label>(j)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001j"></graphic> </fig> <fig id="fig1k"> <label>(k)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001k"></graphic> </fig> <fig id="fig1l"> <label>(左)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001l"></graphic> </fig> <fig id="fig1m"> <label>(m)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.001m"></graphic> </fig> </fig-group> </sec> <sec id="sec3.2"> <title>3.2。常氧和缺氧条件下培养npc的蛋白表达据/title> <p>Western blotting分析了在常氧和缺氧条件下Sprague-Dawley大鼠NPCs中是否也表达了这些蛋白。值得注意的是，推荐的年轻健康鼻咽癌表型标记也在常氧和缺氧条件下表达。western blotting分析结果与qPCR结果一致，缺氧条件下表达量高于正常条件下。缺氧条件下KRT18、KRT19和Shh的表达水平较低(据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M25"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>)，而胶原II、CD24、HIF-2据italic> α据/italic>， Glut-1, brachyury, HIF-1据italic> α据/italic>、CA3、KRT8、aggrecan和CA12均为阴性(图3)据xref rid="fig2" ref-type="fig"> 2据/xref>)．此外，CA12和aggrecan表达水平显著上调(据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M26"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>)在缺氧条件下(图据xref rid="fig2" ref-type="fig"> 2据/xref>)．据/p> <fig-group id="fig2"> <label>图2据/label> <p>(a)在常氧和缺氧条件下培养的npc的相对蛋白表达。每个样品的蛋白质表达水平归功于内务基因据italic> β据/italic>肌动蛋白。(b)胶原II， (c) glut1， (d) CD24， (e)碳酸酐酶12，(f)短链，(g)聚集蛋白，(h) HIF-1据italic> α据/italic>，（i）HIF-2据italic> α据/italic>（j）碳酸酐酶3，（k）krt8，（l）krt18，（m）krt19和（n）shh。据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M27"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>那据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M28"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>那据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M29"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.001据/mml:mn> </mml:math> </inline-formula>,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M30"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>．据/p> <fig id="fig2a"> <label>(一)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002a"></graphic> </fig> <fig id="fig2b"> <label>(b)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002b"></graphic> </fig> <fig id="fig2c"> <label>(c)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002c"></graphic> </fig> <fig id="fig2d"> <label>(d)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002d"></graphic> </fig> <fig id="fig2e"> <label>(e)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002e"></graphic> </fig> <fig id="fig2f"> <label>(f)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002f"></graphic> </fig> <fig id="fig2g"> <label>(g)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002g"></graphic> </fig> <fig id="fig2h"> <label>(h)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002h"></graphic> </fig> <fig id="fig2i"> <label>(我)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002i"></graphic> </fig> <fig id="fig2j"> <label>(j)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002j"></graphic> </fig> <fig id="fig2k"> <label>(k)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002k"></graphic> </fig> <fig id="fig2l"> <label>(左)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002l"></graphic> </fig> <fig id="fig2m"> <label>(m)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002m"></graphic> </fig> <fig id="fig2n"> <label>(n)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.002n"></graphic> </fig> </fig-group> </sec> <sec id="sec3.3"> <title>３．３．免疫荧光染色显示npc蛋白表达模式据/title> <p>进行免疫荧光分析以鉴定NPC中的蛋白质表达。所有推荐的年轻健康的NP表型标记表达在常氧和缺氧条件下培养的NPC中。免疫荧光染色显示出缺氧条件的表达水平显着增加。藻康，Brachyury，碳酸酐酶3，CD24，胶原II，Glut-1，HIF-1据italic> α据/italic>，HIF-2据italic> α据/italic>、KRT8、KRT18、KRT19和Shh在缺氧条件下表现出广泛的染色(图)据xref rid="fig3" ref-type="fig"> 3.据/xref>)．据/p> <fig-group id="fig3"> <label>图3据/label> <p>免疫荧光法检测常氧和缺氧条件下培养的npc的相对蛋白表达。(a) Aggrecan， (b) brachyury， (c) carbonanhydrase 3， (d) CD24， (e) collagen II， (f) Glut-1， (g) HIF-1据italic> α据/italic>HIF-2 (h)据italic> α据/italic>， (i) KRT8， (j) KRT18， (k) KRT19，和(l)嘘。据/p> <fig id="fig3a"> <label>(一)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003a"></graphic> </fig> <fig id="fig3b"> <label>(b)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003b"></graphic> </fig> <fig id="fig3c"> <label>(c)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003c"></graphic> </fig> <fig id="fig3d"> <label>(d)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003d"></graphic> </fig> <fig id="fig3e"> <label>(e)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003e"></graphic> </fig> <fig id="fig3f"> <label>(f)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003f"></graphic> </fig> <fig id="fig3g"> <label>(g)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003g"></graphic> </fig> <fig id="fig3h"> <label>(h)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003h"></graphic> </fig> <fig id="fig3i"> <label>(我)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003i"></graphic> </fig> <fig id="fig3j"> <label>(j)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003j"></graphic> </fig> <fig id="fig3k"> <label>(k)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003k"></graphic> </fig> <fig id="fig3l"> <label>(左)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.003l"></graphic> </fig> </fig-group> </sec> <sec id="sec3.4"> <title>3．4．常氧和缺氧条件下间充质干细胞的基因表达据/title> <p>采用qPCR方法检测常氧和缺氧条件下sd大鼠骨髓间充质干细胞的基因表达情况。与正常缺氧条件相比，50%或100% NPC条件下MSCs基因表达上调。与对照组（Aggecan，）相比，上调最大的是100％NPC条件培养基（Aggecan，据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M31"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>；brachyury,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M32"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>；胶原蛋白II,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M33"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.001据/mml:mn> </mml:math> </inline-formula>；KRT8,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M34"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>；KRT19,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M35"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.001据/mml:mn> </mml:math> </inline-formula>；嘘,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M36"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>)．与对照组相比，还上调了50％NPC条件培养基条件的表达水平（胶原蛋白II，据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M37"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>；KRT8,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M38"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>；KRT19,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M39"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>)．然而，KRT18的表达水平与其他各自基因的表达水平相反，在50%或100% NPC条件培养基中，在常氧和低氧条件下，KRT18的表达水平均低于对照组(图)据xref rid="fig4" ref-type="fig"> 4.据/xref>)．据/p> <fig-group id="fig4"> <label>图4据/label> <p>QPCR在常氧和缺氧条件下MSCs中相对基因表达的评估，50％或100％NPC条件培养基。每种样品的基因表达水平被标准化为管家基因据italic> β据/italic>肌动蛋白。(a)聚合体:(i)常氧，(ii)缺氧;(b)短时间:(i)常氧，(ii)缺氧;(c)胶原蛋白II:(i)常氧，(II)缺氧;(d) KRT8:(i)常氧，(ii)缺氧;(e) KRT18:(i)常氧，(ii)缺氧;(f) KRT19:(i)常氧，(ii)缺氧;和(g) Shh:(i)常氧，(ii)缺氧。据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M40"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>那据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M41"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>那据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M42"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.001据/mml:mn> </mml:math> </inline-formula>,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M43"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>．据/p> <fig id="fig4a"> <label>(一)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.004a"></graphic> </fig> <fig id="fig4b"> <label>(b)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.004b"></graphic> </fig> <fig id="fig4c"> <label>(c)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.004c"></graphic> </fig> <fig id="fig4d"> <label>(d)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.004d"></graphic> </fig> <fig id="fig4e"> <label>(e)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.004e"></graphic> </fig> <fig id="fig4f"> <label>(f)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.004f"></graphic> </fig> <fig id="fig4g"> <label>(g)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.004g"></graphic> </fig> </fig-group> </sec> <sec id="sec3.5"> <title>3．5．常氧和缺氧条件下间充质干细胞的蛋白表达据/title> <p>进行蛋白质印迹分析以研究蛋白质是否在常氧和缺氧条件下在大鼠骨髓衍生的MSC中表达。重要的是，用50％或100％NPC条件培养基处理后上调表达水平。Western印迹分析的结果与QPCR的结果一致，因为缺氧条件的表达水平高于常规条件。与对照组（Aggecan，）相比，上调最大的是100％NPC条件培养基（Aggecan，据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M44"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>；brachyury,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M45"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.001据/mml:mn> </mml:math> </inline-formula>；胶原蛋白II,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M46"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>；KRT8,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M47"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>；KRT19,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M48"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>；嘘,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M49"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>)．与对照组相比，50% NPC条件培养基中的表达水平也上调(aggrecan，据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M50"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>；胶原蛋白II,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M51"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.001据/mml:mn> </mml:math> </inline-formula>；KRT19,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M52"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>；嘘,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M53"> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>)．此外，KRT18的表达水平与qPCR分析结果一致，50%或100% NPC条件培养基在常氧和缺氧条件下均低于对照组(图)据xref rid="fig5" ref-type="fig"> 5.据/xref>)．据/p> <fig-group id="fig5"> <label>图5据/label> <p>（a-c）常氧和缺氧条件下MSCs中相对蛋白质表达的蛋白质印迹评估，具有50％或100％NPC条件培养基。每个样品的蛋白质表达水平归功于内务基因据italic> β据/italic>肌动蛋白。(d)聚合体:(1)常氧，(2)缺氧;(e)短命:(i)常缺氧，(ii)缺氧;(f)胶原蛋白II:(i)常氧，(II)缺氧;(g) KRT8:(i)常氧，(ii)缺氧;(h) KRT18:(i)常氧，(ii)缺氧;(i) KRT19:(i)常氧，(ii)缺氧;和(j)嘘:(i)常氧，(ii)缺氧。据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M54"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> ０．０５据/mml:mn> </mml:math> </inline-formula>那据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M55"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0．01据/mml:mn> </mml:math> </inline-formula>那据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M56"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.001据/mml:mn> </mml:math> </inline-formula>,据inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M57"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗据/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P.据/mml:mi> <mml:mo> 据据/mml:mo> <mml:mn> 0.0001据/mml:mn> </mml:math> </inline-formula>．据/p> <fig id="fig5a"> <label>(一)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005a"></graphic> </fig> <fig id="fig5b"> <label>(b)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005b"></graphic> </fig> <fig id="fig5c"> <label>(c)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005c"></graphic> </fig> <fig id="fig5d"> <label>(d)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005d"></graphic> </fig> <fig id="fig5e"> <label>(e)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005e"></graphic> </fig> <fig id="fig5f"> <label>(f)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005f"></graphic> </fig> <fig id="fig5g"> <label>(g)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005g"></graphic> </fig> <fig id="fig5h"> <label>(h)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005h"></graphic> </fig> <fig id="fig5i"> <label>(我)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005i"></graphic> </fig> <fig id="fig5j"> <label>(j)据/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2020/8882549.fig.005j"></graphic> </fig> </fig-group> </sec> </sec> <sec id="sec4"> <title>4。讨论据/title> <p>关于IVD已有许多研究，但NP和npc的起源仍不清楚。然而，常规NP可以通过分子谱来表征。有证据表明，成熟的NPCs通过脊索谱系分化，而成人的所有细胞(如软骨细胞样细胞)在成熟过程中也从形态和大小不同的脊索谱系分化。这些研究还表明，某些标记对npc更有特异性[据xref ref-type="bibr" rid="B23"> 23据/xref>-据xref ref-type="bibr" rid="B30"> 30.据/xref>］.NPs位于缺氧环境中，适应IVD微环境。据/p> <p>MSC是IVD再生的潜在细胞类型。在可用的细胞源中，经常使用骨髓衍生的MSC。许多研究报道，MSCs对NPC表型具有稳健的分化能力，其在临床试验中已被证明是可用于临床试验。为了更好地理解MSC分化为NP样细胞，我们研究了50％或100％NPC条件培养基对MSC的影响。一些先前的研究表明，据据据说据该禁止细胞和诺奇细胞条件培养基对IVD变性的治疗具有积极影响[据xref ref-type="bibr" rid="B31"> 31据/xref>那据xref ref-type="bibr" rid="B32"> 32据/xref>］.然而，这些积极作用是否适用于间充质干细胞尚不清楚。Aggrecan和collagen II表现出与健康鼻咽癌表型相关的增强表达，而MSCs暴露于脊索细胞条件培养基时表现出刺激作用(例如，上调蛋白多糖在IVD中的沉积)[据xref ref-type="bibr" rid="B33"> 33据/xref>］.据/p> <p>我们的研究是在常氧和缺氧条件下进行的。缺氧条件已显示出支持MSC向NPC表型分化的能力[据xref ref-type="bibr" rid="B34"> 34据/xref>］.我们在常氧和缺氧条件下培养了npc和MSCs。我们使用50%或100% NPC条件培养基(第3段)处理间充质干细胞。鼻咽癌条件培养基对间充质干细胞分化有更积极的影响。在正常NP中，Aggrecan和collagen II明显表达，在IVD变性中观察到Aggrecan合成的丢失[据xref ref-type="bibr" rid="B35"> 35据/xref>］.也有证据表明HIF-1的常氧依赖性稳定据italic> α据/italic>驱动代谢糖酵解，可以帮助调节npc中聚集蛋白基因的表达[据xref ref-type="bibr" rid="B36"> 36据/xref>］.据报道，在IVD退行性变期间，细胞衰老增加，aggrecan和collagen II的产生减少[据xref ref-type="bibr" rid="B37"> 37据/xref>］.在我们的研究中，蛋白和胶原蛋白II在缺氧条件下显示出明显的上调，然后用50％或100％NPC条件培养基处理。统称，我们的研究表明，NPC条件培养基可以通过MSC分化对健康NPC表型来促进再生。据/p> <p>我们的研究结果与其他有关脊索细胞再生作用的研究结果一致;具体来说，鼻咽癌条件培养基被推测含有某些营养成分和分泌性生长因子[据xref ref-type="bibr" rid="B16"> 16据/xref>那据xref ref-type="bibr" rid="B38"> 38据/xref>］.我们以前的研究表明，MSCS通过维持生理过程来保存正常的NP组织稳定性来发挥至关重要的作用[据xref ref-type="bibr" rid="B39"> 39据/xref>］.然而，该研究也表明，鼻咽癌衰老导致IVD变性，而预防这种衰老可以减少IVD变性[据xref ref-type="bibr" rid="B40"> 40据/xref>］.值得注意的是，我们的研究表明，在缺氧条件下，100% NPC条件培养基可以抑制间充质干细胞的衰老。据/p> <p>为了鉴定年轻健康NPC的推荐表型标记，我们还检测了常氧和低氧培养条件下NPC标记的表达。我们的研究表明，在缺氧条件下培养NPCs时，NP标记物显著上调。FOX1、PAX1和CA12在npc中高表达[据xref ref-type="bibr" rid="B30"> 30.据/xref>),而HIF-1据italic> α据/italic>在代谢上适应低氧和营养缺乏的条件[据xref ref-type="bibr" rid="B36"> 36据/xref>］.NP是IVD中最大的无血管组织，通过HIF-1的表达在生理上适应于在缺氧微环境中生存据italic> α据/italic>和HIF-2据italic> α据/italic>．HIF-2的表达据italic> α据/italic>由nf-受到监管据italic> κ据/italic>B途径，其中HIF-2据italic> α据/italic>在缺氧条件下降低水平[据xref ref-type="bibr" rid="B41"> 41据/xref>那据xref ref-type="bibr" rid="B42"> 42据/xref>］.我们的研究结果表明，MSC的外植能增强分化向鼻咽癌表型的能力，促进IVD的再生。细胞外基质的减少是另一个重要的考虑因素。IVD变性过程中促炎细胞因子不稳定性影响椎间盘细胞介导的细胞外基质合成代谢和分解代谢之间的平衡[据xref ref-type="bibr" rid="B43"> 43据/xref>那据xref ref-type="bibr" rid="B44"> 44据/xref>］.因此，抑制这些炎性细胞因子的病理过程可能会刺激间充质干细胞的分化，导致细胞外基质沉积增强。值得注意的是，我们的结果显示aggrecan和collagen II的表达上调，这可以促进基质的形成。据/p> <p>Shh和brachyury在发育中的脊索中表达，它们是脊索鞘形成和NP模式所必需的[据xref ref-type="bibr" rid="B45"> 45据/xref>-据xref ref-type="bibr" rid="B47"> 47据/xref>］.由脊索表达的转录因子以及NP图案化因子（SHH和BRACHYURY）的存在，导游NPC分化和生存。Shh和Brachyury的表达水平是关于NPC本体论的信息水平[据xref ref-type="bibr" rid="B47"> 47据/xref>］.Shh和brachyury水平随着年龄和IVD变性而下调[据xref ref-type="bibr" rid="B30"> 30.据/xref>］.brachyury, aggrecan, and chondroitin sulfate的表达水平升高是由老化椎间盘Wnt信号激活引起的[据xref ref-type="bibr" rid="B48"> 48据/xref>］.一些研究报告说，Brachyury也在一些成熟的NPS中表达[据xref ref-type="bibr" rid="B49"> 49据/xref>那据xref ref-type="bibr" rid="B50"> 50据/xref>］.在Tang等人的研究中，Brachyury在开发人NP组织中表达[据xref ref-type="bibr" rid="B51"> 51据/xref>］.因此，NP标记Shh和brachyury的表达提示我们的研究中存在脊索细胞标记，证实了前人研究的发现[据xref ref-type="bibr" rid="B29"> 29据/xref>那据xref ref-type="bibr" rid="B30"> 30.据/xref>那据xref ref-type="bibr" rid="B52"> 52据/xref>］.此外，在100% NPC条件培养基处理的MSCs中，brachyury和Shh基因的表达量显著提高。这些结果表明MSC向np样表型分化。据/p> <p>细胞角蛋白(KRT8、KRT18和KRT19)以前被鉴定为大鼠npc的标志物。这些基因也在正常的上皮细胞中表达，推测为人类脊索特异标记，尽管KRT19单独在人类npc中得到证实。然而，KRT19在衰老椎间盘中表达减少[据xref ref-type="bibr" rid="B24"> 24据/xref>那据xref ref-type="bibr" rid="B53"> 53据/xref>那据xref ref-type="bibr" rid="B54"> 54据/xref>］.Minogue等人的微阵列研究。鉴定了几种基因的NP特异性表达模式，包括KRT8，KRT18和KRT19，在牛NPC中[据xref ref-type="bibr" rid="B49"> 49据/xref>］.细胞角蛋白具有独特的细胞骨架功能，可帮助维持稳定的细胞结构，调节Fas介导的细胞凋亡，并调节细胞尺寸和蛋白质合成[据xref ref-type="bibr" rid="B55"> 55据/xref>］.它们在组织发育和分化中也发挥着重要作用。KRT8、KRT18和KRT19在大鼠和人类npc中均被识别[据xref ref-type="bibr" rid="B24"> 24据/xref>那据xref ref-type="bibr" rid="B25"> 25据/xref>那据xref ref-type="bibr" rid="B56"> 56据/xref>］.Rodrigues-Pinto等报道，KRT8、KRT18和KRT19在IVD脊索细胞中均有表达[据xref ref-type="bibr" rid="B57"> 57据/xref>］.在最近的一项研究中，KRT8和KRT18在npc中均可检测到，而不管年龄或退化程度如何，而KRT19在老年IVD中表达增强[据xref ref-type="bibr" rid="B29"> 29据/xref>］.事实上，KRT8、KRT18和KRT19在npc缺氧条件下表达显著升高。这些结果与MSC表达一致，除了KRT18。通过qPCR和western blotting分析，KRT18在常氧和低氧条件下表达均较低。IVD的缺氧环境促进个体发育和细胞功能的维持。据/p> <p>在本研究中，我们评估了推荐的NP表型标记，并研究了鼻咽癌条件培养基在常氧和缺氧环境下对MSCs的影响。我们的结论是，这些推荐的表型标记在常氧和低氧培养条件下都能表达，并且鼻咽癌条件培养基中含有一个影响MSCs中基因和蛋白表达的分泌因子。因此，分泌因子可能促进间充质干细胞分化为np样表型。据/p> </sec> <sec id="sec5"> <title>5.结论据/title> <p>我们的研究提供了有助于鉴定健康鼻咽癌表型的数据。我们的结论是，npc表达功能活跃的HIF-1据italic> α据/italic>，HIF-2据italic> α据/italic>在常氧和低氧条件下，glut1、aggrecan、collagen II、Shh、brachyury、KRT8、KRT18、KRT19、CA3、CA12和CD24的表达均明显增加。此外，NPC条件培养基促进间充质干细胞向np样细胞分化。最后，本研究表明，npc和MSCs能够适应缺氧微环境，缺氧刺激这些细胞维持其特定特性。本研究为IVD退行性变的细胞治疗提供了科学依据。据/p> </sec> <back> <sec sec-type="data-availability"> <title>数据可用性据/title> <p>可根据要求提供数据(详细联系信息:Arjun Sinkemani, sinkemani@hotmail.com)。据/p> </sec> <sec sec-type="COI-statement"> <title>利益冲突据/title> <p>作者声明他们没有利益冲突。据/p> </sec> <ack> <title>致谢据/title> <p>国家自然科学基金项目(no . 81572170, no . 81572190, no . 81702190, no . 81702203, no . 81702201);中央高校基本科研业务费专项资金和江苏省研究生科研与实践创新计划项目(no . KYLX16_0302, no . 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