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干细胞国际

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10.1155 / 2021/8888575

8888575

研究文章

VEGF对间充质干细胞细胞介导降级iPS细胞衍生Nor1-Dependent肥大的心肌细胞

菲利普

丹尼斯

¹ Holthaus

米歇尔

¹ Basoah

维达

¹ Pfannkuche

库尔特

² Suhr

劳拉

¹ Wahlers

托尔斯滕

https://orcid.org/0000 - 0001 - 6467 - 3544 Paunel-Gorgulu

Adnana

Tamama

Kenichi

^{1

心胸外科部门

科隆大学的心脏中心

科隆

德国

uni-koeln.de} ^{2

中心生理学和病理生理学

神经生理学研究所

科隆大学

医学院

科隆

德国

uni-koeln.de}

2021年

10 4 2021年

2021年 10 8 2020年 2 3 2021年 24 3 2021年 10 4 2021年

2021年

这是一个开放的文章在知识共享归属许可下发布的,它允许无限制的使用,分布和繁殖在任何媒介,提供最初的工作是正确的引用。

心肌肥厚是心脏出现在许多疾病,代表不良心血管结果的重要因素。关于治疗干预,间充质干细胞(msc)建议大大降低心脏肥大和发展为心力衰竭。预处理的msc以前证明高度提高旁分泌活动导致调制的免疫反应和疾病的进展。在这里,我们研究了骨骨髓来源预处理msc对过分生长的影响诱导多功能干细胞心肌细胞(iPS-CM),也试图识别MSC-derived antihypertrophic分子。去氧肾上腺素(PE)被用来诱导小鼠iPS-CM肥大,和肥大的标志是由微阵列分析。小鼠与干扰素- msc治疗 γ和il - 1 β以提高其旁分泌活性和转录分析是由微阵列分析。过分生长iPS-CM随后cocultured预处理msc和MSC-conditioned中等(CM),分别。影响过分生长iPS-CM量化细胞区域,研究了实时聚合酶链反应和免疫印迹。在一些实验中,细胞被孵化的分数MSC-CM通过超滤或MSC-CM补充与抑制性抗体。细胞内和细胞外的血管内皮生长因子(VEGF)水平进行评估通过免疫印迹和ELISA。iPS-CM PE-induced肥大是相关的upregulation neuron-derived孤儿受体(Nor1)表达式,Akt激活,抑制iPS-CM强烈阻止肥大感应。VEGF分泌预处理msc引起肥大iPS-CM回归,和之间的负相关 Nor1表达式可以证明和肥厚性增长。我们的研究结果表明 Nor1表达强烈支持iPS-CM肥大。此外,检查参与组成分泌腺的肥大的预先处理这些msc触发回归iPS-CM VEGF-dependent的方式。我们建议的交付检查参与组成分泌腺MSC-derived可能代表限制心脏肥大的治疗策略。然而,额外的在活的有机体内需要研究来证明这一假设。德意志Forschungsgemeinschaft 德国心脏研究基金会 F / 06/16 1。介绍<gydF4y2Ba/title> <p>左心室肥厚(LVH)是一种常见的心脏疾病的多种形式的表现,包括心肌梗塞、高血压(<gydF4y2Baxref ref-type="bibr" rid="B1"> 1<gydF4y2Ba/xref>]。人们普遍认为是发展的一个主要危险因素心脏衰竭和心脏猝死代表一个确定的心血管发病率和死亡率的预测。LVH是一个复杂和多因子的条件包括一个自适应重构的过程,这通常是一种代偿机制,以应对增加血流动力学负荷(<gydF4y2Baxref ref-type="bibr" rid="B2"> 2<gydF4y2Ba/xref>]。虽然称为补偿性,延长肥大增加的风险发展为心力衰竭失代偿性肥大。LVH是伴随着各种心脏和分子变化,包括增加蛋白质合成、细胞大小和炎症和纤维发生的反应导致心肌重塑和随后的心室功能障碍(<gydF4y2Baxref ref-type="bibr" rid="B1"> 1<gydF4y2Ba/xref>]。LVH的炎症被证实是一个突出的特点在动物(<gydF4y2Baxref ref-type="bibr" rid="B3"> 3<gydF4y2Ba/xref>和人类研究<gydF4y2Baxref ref-type="bibr" rid="B4"> 4<gydF4y2Ba/xref>]。增加墙应力与LV过载促进改造过程表现为促炎细胞因子表达增加,白细胞浸润,心肌的破坏。因为各种各样的信号通路已经被证明参与心脏肥大的发展(<gydF4y2Baxref ref-type="bibr" rid="B5"> 5<gydF4y2Ba/xref>),理解机制的发展心脏肥大治疗心血管疾病至关重要。因此,逆转心肌肥厚的被认为是一个治疗策略,减少不良改造和预防心脏衰竭(<gydF4y2Baxref ref-type="bibr" rid="B6"> 6<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>NR4A孤儿核受体亚由高度同源受体Nur77 (NR4A1) Nurr1 (NR4A2)和Nor1 (NR4A3)可由各种刺激,包括生长因子、激素、和炎症信号。最近,有很多关注这些受体在心血管系统的功能<gydF4y2Baxref ref-type="bibr" rid="B7"> 7<gydF4y2Ba/xref>]。Nor1显示调节的基本生物过程包括炎症(<gydF4y2Baxref ref-type="bibr" rid="B8"> 8<gydF4y2Ba/xref>,已经提供了第一个证据prohypertrophic属性(<gydF4y2Baxref ref-type="bibr" rid="B9"> 9<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B10"> 10<gydF4y2Ba/xref>]。治疗策略针对肥厚性标记抑制炎性反应可能持有承诺LVH的有益的干预。在这种背景下,巨噬细胞表型的调制提出了作为一种新的治疗方法,当这些细胞被认为是心血管疾病的关键球员。心肌炎症加剧了由促炎的microrna表达M1 - 155巨噬细胞诱导心脏肥大和失败,以应对压力过载(<gydF4y2Baxref ref-type="bibr" rid="B11"> 11<gydF4y2Ba/xref>]。反过来,微rna - 155击倒在巨噬细胞,但在心肌细胞,显著减少炎症,肥大,功能障碍在压力超负荷。最近,回归干细胞移植的心脏肥大和随后的巨噬细胞极化对抗炎M2表型是证明(<gydF4y2Baxref ref-type="bibr" rid="B12"> 12<gydF4y2Ba/xref>]。此外,干细胞疗法目前被认为是治疗心脏衰竭。一些研究,包括临床研究,表明,间充质干细胞(msc)移植可能增强组织灌注、血管生成和保存或重新生成心肌组织(<gydF4y2Baxref ref-type="bibr" rid="B13"> 13<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref ref-type="bibr" rid="B16"> 16<gydF4y2Ba/xref>]。在这种背景下,我们小组的先前的研究已经表明,来源于msc的骨转移的小鼠心肌提高全局函数和改造(<gydF4y2Baxref ref-type="bibr" rid="B17"> 17<gydF4y2Ba/xref>]。msc能分泌细胞因子,生长因子、小分子核糖核酸,和液有效改善新生血管性形成、衰减炎症和不良重塑,诱导内源性心脏再生。相反,检查参与组成分泌腺的骨骨髓来源msc被发现支持一个免疫抑制环境(<gydF4y2Baxref ref-type="bibr" rid="B18"> 18<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref ref-type="bibr" rid="B20"> 20.<gydF4y2Ba/xref>]。目前,msc仍然是最适合临床治疗(<gydF4y2Baxref ref-type="bibr" rid="B21"> 21<gydF4y2Ba/xref>]。预处理的msc高度增加其功效<gydF4y2Baitalic> 在体外<gydF4y2Ba/italic>和<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>,从而防止损失的生物功能,提高其生物活性,为临床使用和代表一个更有吸引力的战略(<gydF4y2Baxref ref-type="bibr" rid="B22"> 22<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>在这项研究中,我们已经建立了一个<gydF4y2Baitalic> 在体外<gydF4y2Ba/italic>心脏肥大模型小鼠心肌细胞“诱导多能性”细胞衍生的基础上(iPS-CM),研究了肥厚性反应。我们进一步研究了预处理msc是否会扭转iPS-CM肥大和确定VEGF MSC-mediated肥大回归的主要因素。<gydF4y2Ba/p> </sec> <sec id="sec2"> <title>2。材料和方法<gydF4y2Ba/title> <sec id="sec2.1"> <title>2.1。小鼠iPS-CM和肥大细胞培养条件归纳<gydF4y2Ba/title> <p>分化,nonproliferative小鼠iPS-CM请提供的库尔特博士Pfannkuche(科隆大学神经生理学研究所)。这些细胞表现出自发性收缩和正常生理功能就是明证动作电位,功能激素调节和敏感性离子通道阻滞剂(<gydF4y2Baxref ref-type="bibr" rid="B23"> 23<gydF4y2Ba/xref>]。细胞被播种fibronectin-coated文化菜(2.6<gydF4y2Baitalic> μ<gydF4y2Ba/italic>克/厘米<gydF4y2Basup>2<gydF4y2Ba/sup>)和培养与GlutaMAX IMDM介质(Gibco), 20% FCS (PAN),不必要的氨基酸(Gibco) 1%, 0.1毫米2-mercaptoethanol (Gibco)、青霉素、链霉素和100 U /毫升(Sigma-Aldrich)。中每天都是新的。诱导肥大,细胞被饿死在IMDM介质与GlutaMAX补充1% FCS 24 h和进一步处理L-phenylephrine (PE、100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米,Sigma-Aldrich)额外的24小时。在一些实验中,过分生长iPS-CM培养在培养基补充MSC-conditioned介质(CM)或从MSC-CM和PE(100分数<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米)多克隆山羊anti-mouse VEGF的存在与否<gydF4y2Basub>164年<gydF4y2Ba/sub>(研发系统)的抗体。<gydF4y2Ba/p> </sec> <sec id="sec2.2"> <title>2.2。隔离、表征和激活骨骨髓来源msc<gydF4y2Ba/title> <p>隔离和表征的老鼠骨骨髓来源msc以前我们小组报告的细节。细胞阳性古典MSC标记包括本来CD49e, CD44, CD29,没有表达CD45和CD11b,分别。证实了MSC表型分析其潜在分化为软骨细胞,脂肪细胞,成骨细胞(<gydF4y2Baxref ref-type="bibr" rid="B20"> 20.<gydF4y2Ba/xref>]。对于实验,msc刺激了30 ng / ml重组小鼠干扰素-<gydF4y2Baitalic> γ<gydF4y2Ba/italic>(PeproTech)和3 ng / ml重组小鼠il - 1<gydF4y2Baitalic> β<gydF4y2Ba/italic>(PeproTech) MSC培养基(Pan-Biotech)补充2.5 ng / ml人类基本的纤维母细胞生长因子FGF (FGF-b PeproTech), 100 U /毫升青霉素和10<gydF4y2Baitalic> μ<gydF4y2Ba/italic>g / ml链霉素(Sigma-Aldrich) 24 h。预处理msc具有抗炎和免疫调节能力<gydF4y2Baxref ref-type="bibr" rid="B20"> 20.<gydF4y2Ba/xref>)和用于coculture实验。<gydF4y2Ba/p> <p>先决条件获得MSC-CM, msc进一步采用无血清培养IMDM介质稳定谷氨酰胺(Gibco)额外的24小时。然后,上层的收集和储存在-80°C,直到进一步的处理。证明如果msc保留它们的免疫调节特性血清饥饿后,亚硝酸盐含量文化上层的量化使用修改后的格里斯试剂(Sigma-Aldrich)已经描述(<gydF4y2Baxref ref-type="bibr" rid="B20"> 20.<gydF4y2Ba/xref>]。上层清液含有高浓度的亚硝酸盐,指示调节<gydF4y2Baitalic> 伊诺<gydF4y2Ba/italic>表达式,用于实验。<gydF4y2Ba/p> </sec> <sec id="sec2.3"> <title>2.3。Coculture条件<gydF4y2Ba/title> <p>coculture实验,过分生长iPS-CM的先决条件是间接cocultured msc(5: 1比例)IMDM中补充FCS和100年的1%<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M PE 24 h。为此,条件msc被transwell插入在0.4<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米孔隙大小(康宁)来避免直接的细胞间的相互作用。<gydF4y2Ba/p> </sec> <sec id="sec2.4"> <title>2.4。免疫荧光分析<gydF4y2Ba/title> <p>iPS-CM (<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"> <mml:mn> 1。5<gydF4y2Ba/mml:mn> <mml:mo> ×<gydF4y2Ba/mml:mo> <mml:msup> <mml:mrow> <mml:mn> 10<gydF4y2Ba/mml:mn> </mml:mrow> <mml:mrow> <mml:mn> 4<gydF4y2Ba/mml:mn> </mml:mrow> </mml:msup> </mml:math> </inline-formula>)是生长在fibronectin-coated 12-well板盖玻片,缺少24小时,处理100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M PE FCS的1%。预先处理,细胞被cocultured msc MSC-CM处理或分次上层清液,分别在体育的存在。24小时后,细胞被固定为4%多聚甲醛0.1% 20分钟和permeabilized Triton x - 100,和非特异性结合位点被封锁使用1% BSA在PBS稀释。细胞进一步孵化Alexa萤石®555 phalloidin(热科学)f -肌动蛋白阻止20分钟解决方案污点,其次是与DAPI对比染色。盖玻片被清洗和安装在玻璃幻灯片。荧光图像获得使用尼康Eclipse Ti-U倒置显微镜(Eclipse Ti-U 100、尼康、德国)使用软件NIS-Elements 3.00版。细胞表面区域(<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米<gydF4y2Basup>2<gydF4y2Ba/sup>)100或更高的细胞/随机选择的10个领域里的测量条件。<gydF4y2Ba/p> </sec> <sec id="sec2.5"> <title>2.5。实时聚合酶链反应<gydF4y2Ba/title> <p>总RNA从iPS-CM孤立使用RNeasy迷你包(试剂盒)和反向转录与高容量cDNA逆转录工具包(应用生物系统公司)。目标基因被实时PCR扩增使用StepOnePlus或QuantStudio 3实时PCR系统(应用生物系统公司)和电力SYBR绿色PCR反应混合液(应用生物系统公司)。以下<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>引物被使用::5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> </mml:math> </inline-formula>-AGACGCCGAAACCGATGT-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> </mml:math> </inline-formula>牧师:5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> </mml:math> </inline-formula>-TCGGACAAGGGCATTCA-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> </mml:math> </inline-formula>。基因表达是规范化18 s rRNA。所有样品都是一式三份。褶皱表达式计算使用<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"> <mml:msup> <mml:mrow> <mml:mn> 2<gydF4y2Ba/mml:mn> </mml:mrow> <mml:mrow> <mml:mo> −<gydF4y2Ba/mml:mo> <mml:mi> Δ<gydF4y2Ba/mml:mi> <mml:mi> Δ<gydF4y2Ba/mml:mi> </mml:mrow> </mml:msup> <mml:msub> <mml:mrow> <mml:mtext> C<gydF4y2Ba/mml:mtext> </mml:mrow> <mml:mrow> <mml:mtext> T<gydF4y2Ba/mml:mtext> </mml:mrow> </mml:msub> </mml:math> </inline-formula>方法。<gydF4y2Ba/p> </sec> <sec id="sec2.6"> <title>2.6。微阵列分析<gydF4y2Ba/title> <p>RNA提取使用RNeasy迷你包(试剂盒),已经没有DNA和DNA被污染的细胞工具(Ambion)。过分生长的基因表达分析iPS-CM使用GeneChip老鼠基因组430.2执行预先处理和msc (Affymetrix)或Clariom年代化验(热费希尔)基因表达Affymetrix设施由教授Agapios Sachinidis(分子医学中心,科隆)。RNA从3 - 5个独立实验使用。<gydF4y2Ba/p> </sec> <sec id="sec2.7"> <title>2.7。核转染<gydF4y2Ba/title> <p>来击倒<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>表情,iPS-CM被播种在6-well盘子或者涂盖玻片在IMDM 12-well盘子和培养介质+ 1% FCS。转染已经使用OptiMEM执行媒介(Gibco)和Lipofectamine RNAiMAX试剂(英杰公司)根据制造商的指示。细胞转染为5.5 nM消音器选择Nor1核小干扰rna (Ambion)和消音器选择消极的控制,分别和孵化24小时37°C和5%股份有限公司<gydF4y2Basub>2<gydF4y2Ba/sub>。然后,100年<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M PE是额外添加和细胞培养24小时。转染效率被实时PCR验证。盖玻片上培养的细胞用于immunofluorescent分析。<gydF4y2Ba/p> </sec> <sec id="sec2.8"> <title>2.8。免疫印迹<gydF4y2Ba/title> <p>细胞细胞溶解在缓冲区里帕补充蛋白酶和磷酸酶抑制剂鸡尾酒(细胞信号技术)和用,和蛋白质浓度被使用皮尔斯BCA量化分析工具(热费希尔科学)。蛋白质混合物是由sds - page分离和转移到硝酸纤维素(0.2<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米)。膜被封锁与阻断缓冲区和进一步孵化一夜之间在4°C以下抗体:兔子anti-mouse phospho-Akt (Ser473), NF -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B p65, pNF——虽然<gydF4y2Baitalic> κ<gydF4y2Ba/italic>HIF-1 B p65 (Ser536)<gydF4y2Baitalic> α<gydF4y2Ba/italic>(细胞信号技术)、多克隆兔anti-mouse Nor1 (Abcam)和多克隆山羊anti-mouse VEGF<gydF4y2Basub>164年<gydF4y2Ba/sub>抗体(研发系统)。孵化后,HRP-conjugated山羊anti-rabbit (Dako)或马抗体(向量实验室)二级抗体膜开发与UptiLight合污点化学发光ECL衬底(Uptima)。规范化蛋白表达,屁股被剥夺,reprobed GAPDH或<gydF4y2Baitalic> β<gydF4y2Ba/italic>肌动蛋白和Akt,分别使用鼠标anti-GAPDH抗体(罗福斯生物)和anti-mouse<gydF4y2Baitalic> β<gydF4y2Ba/italic>肌动蛋白和兔anti-mouse Akt抗体(细胞信号技术)。<gydF4y2Ba/p> </sec> <sec id="sec2.9"> <title>2.9。ELISA<gydF4y2Ba/title> <p>VEGF水平的量化通过使用鼠标DuoSet ELISA包根据制造商的指示(研发系统)。<gydF4y2Ba/p> </sec> <sec id="sec2.10"> <title>2.10。超滤<gydF4y2Ba/title> <p>超滤单元与各种达标(Vivaspin 6 20,缝匠肌、德国)首次通过离心法纯水清洗膜。然后分析离心机中<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"> <mml:mn> 6000年<gydF4y2Ba/mml:mn> <mml:mo> ×<gydF4y2Ba/mml:mo> <mml:mi> g<gydF4y2Ba/mml:mi> </mml:math> </inline-formula>直到上层清液达到初始体积的十分之一,集中上层清液和滤液收集分数在塑料管和用于实验。<gydF4y2Ba/p> </sec> <sec id="sec2.11"> <title>2.11。统计分析<gydF4y2Ba/title> <p>数据分析与GraphPad棱镜5软件。实验数据与平均数标准误差表示为手段(SEM)。未配对的两组数据进行了分析使用未配对<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"> <mml:mi> t<gydF4y2Ba/mml:mi> </mml:math> </inline-formula>以及。的一个示例<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"> <mml:mi> t<gydF4y2Ba/mml:mi> </mml:math> </inline-formula>以及使用当样本相对于参考控制样本(设置为1)。正态分布未配对数据分析了多个组的使用单向方差分析与Newman-Keuls事后测试。一个<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"> <mml:mi> p<gydF4y2Ba/mml:mi> </mml:math> </inline-formula>值不到0.05被认为是具有统计学意义。<gydF4y2Ba/p> </sec> </sec> <sec id="sec3"> <title>3所示。结果<gydF4y2Ba/title> <sec id="sec3.1"> <title>3.1。肥大的识别标记PE-Stimulated iPS-CM<gydF4y2Ba/title> <p>心脏肥大是由众多转录、生化和结构转换包括增加细胞大小,增强蛋白质合成和肌动蛋白细胞骨架的改建。然而,一个<gydF4y2Baitalic> 在体外<gydF4y2Ba/italic>基于小鼠iPS-CM肥大模型到目前为止没有描述。因此,我们第一次开始识别基因标记iPS-CM监管的PE肥厚性物质。通过执行微阵列分析,我们发现154个基因是调控(褶皱变化表达式2 >或< PE(表2)<gydF4y2Baxref rid="tab1" ref-type="table"> 1<gydF4y2Ba/xref>,图<gydF4y2Baxref rid="fig1a" ref-type="fig"> 1(一)<gydF4y2Ba/xref>)。在46调节基因,基因<gydF4y2Baitalic> Nr4a3<gydF4y2Ba/italic>,编码neuron-derived孤儿受体1 (Nor1),被发现是最调节基因(~ 3年来感应)PE-treated iPS-CM。Upregulation额外的基因参与肥厚性细胞生长,如<gydF4y2Baitalic> Nppb<gydF4y2Ba/italic>(法国),<gydF4y2Baitalic> Myh7<gydF4y2Ba/italic>(<gydF4y2Baitalic> β<gydF4y2Ba/italic>mhc),<gydF4y2Baitalic> Gja1<gydF4y2Ba/italic>(Cx43),<gydF4y2Baitalic> Nppa<gydF4y2Ba/italic>(ANP) [<gydF4y2Baxref ref-type="bibr" rid="B24"> 24<gydF4y2Ba/xref>相比),较低<gydF4y2Baitalic> Nor1 / Nr4a3<gydF4y2Ba/italic>表达水平(图<gydF4y2Baxref rid="fig1b" ref-type="fig"> 1 (b)<gydF4y2Ba/xref>)。在这些结果的基础上,我们决定使用<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>作为一个有价值的iPS-CM肥厚性细胞生长状态的标志。证实了PE的upregulation实时PCR(图<gydF4y2Baxref rid="fig1c" ref-type="fig"> 1 (c)<gydF4y2Ba/xref>)。此外,Nor1蛋白质在整理iPS-CM显著增加,并增加激酶Akt的活动,但不是兵,可以发现(图<gydF4y2Baxref rid="fig1d" ref-type="fig"> 1 (d)<gydF4y2Ba/xref>)。Nor1表达式显示正相关的细胞表面积iPS-CM肌动蛋白染色和免疫荧光(图证明了这一点<gydF4y2Baxref rid="fig1e" ref-type="fig"> 1 (e)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> <table-wrap id="tab1"> <label>表1<gydF4y2Ba/label> <p>差异基因表达在PE-treated iPS-CM。<gydF4y2Ba/p> <table> <thead> <tr> <th align="left">基因符号<gydF4y2Ba/th> <th align="center">基因身份证<gydF4y2Ba/th> <th align="center">100年体育<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M avg (log2)<gydF4y2Ba/th> <th align="center">控制avg (log2)<gydF4y2Ba/th> <th align="center">褶皱变化<gydF4y2Ba/th> </tr> </thead> <tbody> <tr> <td align="left">Nr4a3<gydF4y2Ba/td> <td align="center">1438796 _at<gydF4y2Ba/td> <td align="center">7.93<gydF4y2Ba/td> <td align="center">5。4<gydF4y2Ba/td> <td align="center">5.78<gydF4y2Ba/td> </tr> <tr> <td align="left">Creb3l1<gydF4y2Ba/td> <td align="center">1419295 _at<gydF4y2Ba/td> <td align="center">8.49<gydF4y2Ba/td> <td align="center">6.31<gydF4y2Ba/td> <td align="center">4.53<gydF4y2Ba/td> </tr> <tr> <td align="left">Mgarp<gydF4y2Ba/td> <td align="center">1420774 _a_at<gydF4y2Ba/td> <td align="center">7.01<gydF4y2Ba/td> <td align="center">4.87<gydF4y2Ba/td> <td align="center">4.39<gydF4y2Ba/td> </tr> <tr> <td align="left">dn<gydF4y2Ba/td> <td align="center">1456379 _x_at<gydF4y2Ba/td> <td align="center">5.75<gydF4y2Ba/td> <td align="center">3.72<gydF4y2Ba/td> <td align="center">4.11<gydF4y2Ba/td> </tr> <tr> <td align="left">Pde4d<gydF4y2Ba/td> <td align="center">1435280 _at<gydF4y2Ba/td> <td align="center">8.62<gydF4y2Ba/td> <td align="center">6.67<gydF4y2Ba/td> <td align="center">3.87<gydF4y2Ba/td> </tr> <tr> <td align="left">韩国仁荷<gydF4y2Ba/td> <td align="center">1422728 _at<gydF4y2Ba/td> <td align="center">9.91<gydF4y2Ba/td> <td align="center">7.97<gydF4y2Ba/td> <td align="center">3.86<gydF4y2Ba/td> </tr> <tr> <td align="left">dn<gydF4y2Ba/td> <td align="center">1423671 _at<gydF4y2Ba/td> <td align="center">6.84<gydF4y2Ba/td> <td align="center">5.11<gydF4y2Ba/td> <td align="center">3.31<gydF4y2Ba/td> </tr> <tr> <td align="left">Nppb<gydF4y2Ba/td> <td align="center">1450791 _at<gydF4y2Ba/td> <td align="center">9.94<gydF4y2Ba/td> <td align="center">8.22<gydF4y2Ba/td> <td align="center">3所示。3<gydF4y2Ba/td> </tr> <tr> <td align="left">Fam46a<gydF4y2Ba/td> <td align="center">1437868 _at<gydF4y2Ba/td> <td align="center">9.58<gydF4y2Ba/td> <td align="center">7.93<gydF4y2Ba/td> <td align="center">3.14<gydF4y2Ba/td> </tr> <tr> <td align="left">Ajap1<gydF4y2Ba/td> <td align="center">1456197 _x_at<gydF4y2Ba/td> <td align="center">5.08<gydF4y2Ba/td> <td align="center">3.48<gydF4y2Ba/td> <td align="center">3.04<gydF4y2Ba/td> </tr> <tr> <td align="left">Scd1<gydF4y2Ba/td> <td align="center">1415964 _at<gydF4y2Ba/td> <td align="center">10.95<gydF4y2Ba/td> <td align="center">9.42<gydF4y2Ba/td> <td align="center">2。9<gydF4y2Ba/td> </tr> <tr> <td align="left">Slitrk4<gydF4y2Ba/td> <td align="center">1440516 _at<gydF4y2Ba/td> <td align="center">7.52<gydF4y2Ba/td> <td align="center">6.01<gydF4y2Ba/td> <td align="center">2.85<gydF4y2Ba/td> </tr> <tr> <td align="left">Cnn1<gydF4y2Ba/td> <td align="center">1417917 _at<gydF4y2Ba/td> <td align="center">10.04<gydF4y2Ba/td> <td align="center">8.6<gydF4y2Ba/td> <td align="center">2.72<gydF4y2Ba/td> </tr> <tr> <td align="left">Dgkk<gydF4y2Ba/td> <td align="center">1442865 _at<gydF4y2Ba/td> <td align="center">7.08<gydF4y2Ba/td> <td align="center">5.68<gydF4y2Ba/td> <td align="center">2.66<gydF4y2Ba/td> </tr> <tr> <td align="left">Alpl<gydF4y2Ba/td> <td align="center">1423611 _at<gydF4y2Ba/td> <td align="center">7.99<gydF4y2Ba/td> <td align="center">6.58<gydF4y2Ba/td> <td align="center">2.65<gydF4y2Ba/td> </tr> <tr> <td align="left">Clic6<gydF4y2Ba/td> <td align="center">1454866 _s_at<gydF4y2Ba/td> <td align="center">6.12<gydF4y2Ba/td> <td align="center">4所示。8<gydF4y2Ba/td> <td align="center">2。5<gydF4y2Ba/td> </tr> <tr> <td align="left">Mapk10<gydF4y2Ba/td> <td align="center">1437195 _x_at<gydF4y2Ba/td> <td align="center">6.56<gydF4y2Ba/td> <td align="center">5.26<gydF4y2Ba/td> <td align="center">2.46<gydF4y2Ba/td> </tr> <tr> <td align="left">Aqp4<gydF4y2Ba/td> <td align="center">1425382 _a_at<gydF4y2Ba/td> <td align="center">8.83<gydF4y2Ba/td> <td align="center">7.54<gydF4y2Ba/td> <td align="center">2.45<gydF4y2Ba/td> </tr> <tr> <td align="left">Ap1s3<gydF4y2Ba/td> <td align="center">1455735 _at<gydF4y2Ba/td> <td align="center">6.36<gydF4y2Ba/td> <td align="center">5.08<gydF4y2Ba/td> <td align="center">2.42<gydF4y2Ba/td> </tr> <tr> <td align="left">Slc16a3<gydF4y2Ba/td> <td align="center">1449005 _at<gydF4y2Ba/td> <td align="center">7.03<gydF4y2Ba/td> <td align="center">5.75<gydF4y2Ba/td> <td align="center">2.41<gydF4y2Ba/td> </tr> <tr> <td align="left">Greb1l<gydF4y2Ba/td> <td align="center">1439341 _at<gydF4y2Ba/td> <td align="center">5.66<gydF4y2Ba/td> <td align="center">4.44<gydF4y2Ba/td> <td align="center">2.32<gydF4y2Ba/td> </tr> <tr> <td align="left">Rgs2<gydF4y2Ba/td> <td align="center">1419248 _at<gydF4y2Ba/td> <td align="center">8.42<gydF4y2Ba/td> <td align="center">7.22<gydF4y2Ba/td> <td align="center">2。3<gydF4y2Ba/td> </tr> <tr> <td align="left">Emilin2<gydF4y2Ba/td> <td align="center">1435264 _at<gydF4y2Ba/td> <td align="center">12<gydF4y2Ba/td> <td align="center">10.82<gydF4y2Ba/td> <td align="center">2.27<gydF4y2Ba/td> </tr> <tr> <td align="left">Bmp7<gydF4y2Ba/td> <td align="center">1418910 _at<gydF4y2Ba/td> <td align="center">7.54<gydF4y2Ba/td> <td align="center">6.39<gydF4y2Ba/td> <td align="center">2.22<gydF4y2Ba/td> </tr> <tr> <td align="left">Krt19<gydF4y2Ba/td> <td align="center">1417156 _at<gydF4y2Ba/td> <td align="center">5.43<gydF4y2Ba/td> <td align="center">4.28<gydF4y2Ba/td> <td align="center">2.22<gydF4y2Ba/td> </tr> <tr> <td align="left">Rgs2<gydF4y2Ba/td> <td align="center">1447830 _s_at<gydF4y2Ba/td> <td align="center">7.06<gydF4y2Ba/td> <td align="center">5.92<gydF4y2Ba/td> <td align="center">2.21<gydF4y2Ba/td> </tr> <tr> <td align="left">Slc7a3<gydF4y2Ba/td> <td align="center">1417022 _at<gydF4y2Ba/td> <td align="center">9.55<gydF4y2Ba/td> <td align="center">8.42<gydF4y2Ba/td> <td align="center">2.19<gydF4y2Ba/td> </tr> <tr> <td align="left">Sox11<gydF4y2Ba/td> <td align="center">1453125 _at<gydF4y2Ba/td> <td align="center">6.79<gydF4y2Ba/td> <td align="center">5.67<gydF4y2Ba/td> <td align="center">2.17<gydF4y2Ba/td> </tr> <tr> <td align="left">Pcdh8<gydF4y2Ba/td> <td align="center">1447825 _x_at<gydF4y2Ba/td> <td align="center">4.64<gydF4y2Ba/td> <td align="center">3.54<gydF4y2Ba/td> <td align="center">2.15<gydF4y2Ba/td> </tr> <tr> <td align="left">Slitrk4<gydF4y2Ba/td> <td align="center">1437744 _at<gydF4y2Ba/td> <td align="center">9.71<gydF4y2Ba/td> <td align="center">8.61<gydF4y2Ba/td> <td align="center">2.13<gydF4y2Ba/td> </tr> <tr> <td align="left">Fndc5<gydF4y2Ba/td> <td align="center">1453135 _at<gydF4y2Ba/td> <td align="center">6.77<gydF4y2Ba/td> <td align="center">5.68<gydF4y2Ba/td> <td align="center">2.12<gydF4y2Ba/td> </tr> <tr> <td align="left">Rgs2<gydF4y2Ba/td> <td align="center">1419247 _at<gydF4y2Ba/td> <td align="center">8.66<gydF4y2Ba/td> <td align="center">7.59<gydF4y2Ba/td> <td align="center">2。1<gydF4y2Ba/td> </tr> <tr> <td align="left">Pcdh8<gydF4y2Ba/td> <td align="center">1417051 _at<gydF4y2Ba/td> <td align="center">4.44<gydF4y2Ba/td> <td align="center">3.38<gydF4y2Ba/td> <td align="center">2.08<gydF4y2Ba/td> </tr> <tr> <td align="left">Bmp7<gydF4y2Ba/td> <td align="center">1432410 _a_at<gydF4y2Ba/td> <td align="center">6.67<gydF4y2Ba/td> <td align="center">5.62<gydF4y2Ba/td> <td align="center">2.07<gydF4y2Ba/td> </tr> <tr> <td align="left">Syt7<gydF4y2Ba/td> <td align="center">1460081 _at<gydF4y2Ba/td> <td align="center">8.3<gydF4y2Ba/td> <td align="center">7.26<gydF4y2Ba/td> <td align="center">2.06<gydF4y2Ba/td> </tr> <tr> <td align="left">Synm<gydF4y2Ba/td> <td align="center">1457275 _at<gydF4y2Ba/td> <td align="center">7.98<gydF4y2Ba/td> <td align="center">6.93<gydF4y2Ba/td> <td align="center">2.06<gydF4y2Ba/td> </tr> <tr> <td align="left">Gp1bb<gydF4y2Ba/td> <td align="center">1422977 _at<gydF4y2Ba/td> <td align="center">6.73<gydF4y2Ba/td> <td align="center">5.69<gydF4y2Ba/td> <td align="center">2.06<gydF4y2Ba/td> </tr> <tr> <td align="left">Bdh1<gydF4y2Ba/td> <td align="center">1452257 _at<gydF4y2Ba/td> <td align="center">9.86<gydF4y2Ba/td> <td align="center">8.83<gydF4y2Ba/td> <td align="center">2.04<gydF4y2Ba/td> </tr> <tr> <td align="left">Pmaip1<gydF4y2Ba/td> <td align="center">1418203 _at<gydF4y2Ba/td> <td align="center">8.49<gydF4y2Ba/td> <td align="center">7.46<gydF4y2Ba/td> <td align="center">2.04<gydF4y2Ba/td> </tr> <tr> <td align="left">Sox11<gydF4y2Ba/td> <td align="center">1429372 _at<gydF4y2Ba/td> <td align="center">6.23<gydF4y2Ba/td> <td align="center">5。2<gydF4y2Ba/td> <td align="center">2.04<gydF4y2Ba/td> </tr> <tr> <td align="left">Kdelr3<gydF4y2Ba/td> <td align="center">1418538 _at<gydF4y2Ba/td> <td align="center">8.77<gydF4y2Ba/td> <td align="center">7.75<gydF4y2Ba/td> <td align="center">2.04<gydF4y2Ba/td> </tr> <tr> <td align="left">Fkbp11<gydF4y2Ba/td> <td align="center">1417267 _s_at<gydF4y2Ba/td> <td align="center">6.51<gydF4y2Ba/td> <td align="center">5.49<gydF4y2Ba/td> <td align="center">2.04<gydF4y2Ba/td> </tr> <tr> <td align="left">Olfml2b<gydF4y2Ba/td> <td align="center">1423915 _at<gydF4y2Ba/td> <td align="center">10.71<gydF4y2Ba/td> <td align="center">9.68<gydF4y2Ba/td> <td align="center">2.03<gydF4y2Ba/td> </tr> <tr> <td align="left">Aqp4<gydF4y2Ba/td> <td align="center">1434449 _at<gydF4y2Ba/td> <td align="center">10.01<gydF4y2Ba/td> <td align="center">8.99<gydF4y2Ba/td> <td align="center">2.03<gydF4y2Ba/td> </tr> <tr> <td align="left">Sprr1a<gydF4y2Ba/td> <td align="center">1449133 _at<gydF4y2Ba/td> <td align="center">7.54<gydF4y2Ba/td> <td align="center">6.53<gydF4y2Ba/td> <td align="center">2.02<gydF4y2Ba/td> </tr> <tr> <td align="left">Synpo<gydF4y2Ba/td> <td align="center">1427045 _at<gydF4y2Ba/td> <td align="center">8.17<gydF4y2Ba/td> <td align="center">7.16<gydF4y2Ba/td> <td align="center">2.02<gydF4y2Ba/td> </tr> <tr> <td align="left">Ddit4l<gydF4y2Ba/td> <td align="center">1451751 _at<gydF4y2Ba/td> <td align="center">6.23<gydF4y2Ba/td> <td align="center">7.23<gydF4y2Ba/td> <td align="center">2<gydF4y2Ba/td> </tr> <tr> <td align="left">Maob<gydF4y2Ba/td> <td align="center">1434354 _at<gydF4y2Ba/td> <td align="center">7.26<gydF4y2Ba/td> <td align="center">8.26<gydF4y2Ba/td> <td align="center">2<gydF4y2Ba/td> </tr> <tr> <td align="left">Mmp2<gydF4y2Ba/td> <td align="center">1416136 _at<gydF4y2Ba/td> <td align="center">5.97<gydF4y2Ba/td> <td align="center">6.97<gydF4y2Ba/td> <td align="center">2<gydF4y2Ba/td> </tr> <tr> <td align="left">Sema5a<gydF4y2Ba/td> <td align="center">1434776 _at<gydF4y2Ba/td> <td align="center">6.18<gydF4y2Ba/td> <td align="center">7.18<gydF4y2Ba/td> <td align="center">2<gydF4y2Ba/td> </tr> <tr> <td align="left">Phkg1<gydF4y2Ba/td> <td align="center">1422315 _x_at<gydF4y2Ba/td> <td align="center">6.46<gydF4y2Ba/td> <td align="center">7.46<gydF4y2Ba/td> <td align="center">-2.01<gydF4y2Ba/td> </tr> <tr> <td align="left">Kcnd2<gydF4y2Ba/td> <td align="center">1422834 _at<gydF4y2Ba/td> <td align="center">6.62<gydF4y2Ba/td> <td align="center">7.62<gydF4y2Ba/td> <td align="center">-2.01<gydF4y2Ba/td> </tr> <tr> <td align="left">Ccdc187<gydF4y2Ba/td> <td align="center">1430052 _at<gydF4y2Ba/td> <td align="center">5.45<gydF4y2Ba/td> <td align="center">6.46<gydF4y2Ba/td> <td align="center">-2.01<gydF4y2Ba/td> </tr> <tr> <td align="left">在你<gydF4y2Ba/td> <td align="center">1437718 _x_at<gydF4y2Ba/td> <td align="center">4.98<gydF4y2Ba/td> <td align="center">5.98<gydF4y2Ba/td> <td align="center">-2.01<gydF4y2Ba/td> </tr> <tr> <td align="left">Shisa9<gydF4y2Ba/td> <td align="center">1435424 _x_at<gydF4y2Ba/td> <td align="center">3.79<gydF4y2Ba/td> <td align="center">4所示。8<gydF4y2Ba/td> <td align="center">-2.01<gydF4y2Ba/td> </tr> <tr> <td align="left">Cdo1<gydF4y2Ba/td> <td align="center">1448842 _at<gydF4y2Ba/td> <td align="center">9.23<gydF4y2Ba/td> <td align="center">10.24<gydF4y2Ba/td> <td align="center">-2.01<gydF4y2Ba/td> </tr> <tr> <td align="left">Phkg1<gydF4y2Ba/td> <td align="center">1425164 _a_at<gydF4y2Ba/td> <td align="center">6.8<gydF4y2Ba/td> <td align="center">7.81<gydF4y2Ba/td> <td align="center">-2.01<gydF4y2Ba/td> </tr> <tr> <td align="left">Epb41l2<gydF4y2Ba/td> <td align="center">1459619 _at<gydF4y2Ba/td> <td align="center">5.89<gydF4y2Ba/td> <td align="center">6.91<gydF4y2Ba/td> <td align="center">-2.01<gydF4y2Ba/td> </tr> <tr> <td align="left">Scn7a<gydF4y2Ba/td> <td align="center">1436043 _at<gydF4y2Ba/td> <td align="center">8.07<gydF4y2Ba/td> <td align="center">9.08<gydF4y2Ba/td> <td align="center">-2.02<gydF4y2Ba/td> </tr> <tr> <td align="left">Fbln2<gydF4y2Ba/td> <td align="center">1423407 _a_at<gydF4y2Ba/td> <td align="center">6.62<gydF4y2Ba/td> <td align="center">7.63<gydF4y2Ba/td> <td align="center">-2.02<gydF4y2Ba/td> </tr> <tr> <td align="left">在你<gydF4y2Ba/td> <td align="center">1456084 _x_at<gydF4y2Ba/td> <td align="center">6.16<gydF4y2Ba/td> <td align="center">7.17<gydF4y2Ba/td> <td align="center">-2.02<gydF4y2Ba/td> </tr> <tr> <td align="left">Clec2l<gydF4y2Ba/td> <td align="center">1433764 _at<gydF4y2Ba/td> <td align="center">7.95<gydF4y2Ba/td> <td align="center">8.97<gydF4y2Ba/td> <td align="center">-2.02<gydF4y2Ba/td> </tr> <tr> <td align="left" rowspan="4">Prss35<gydF4y2Ba/td> <td align="center">1434195 _at<gydF4y2Ba/td> <td align="center">4所示。2<gydF4y2Ba/td> <td align="center">5.22<gydF4y2Ba/td> <td align="center">-2.03<gydF4y2Ba/td> </tr> <tr> <td align="center">1445148 _at<gydF4y2Ba/td> <td align="center">7.17<gydF4y2Ba/td> <td align="center">8.19<gydF4y2Ba/td> <td align="center">-2.03<gydF4y2Ba/td> </tr> <tr> <td align="center">1446742 _at<gydF4y2Ba/td> <td align="center">3.72<gydF4y2Ba/td> <td align="center">4.74<gydF4y2Ba/td> <td align="center">-2.03<gydF4y2Ba/td> </tr> <tr> <td align="center">1439174 _at<gydF4y2Ba/td> <td align="center">3.82<gydF4y2Ba/td> <td align="center">4.84<gydF4y2Ba/td> <td align="center">-2.03<gydF4y2Ba/td> </tr> <tr> <td align="left" rowspan="2">Tuba8<gydF4y2Ba/td> <td align="center">1419518 _at<gydF4y2Ba/td> <td align="center">6.29<gydF4y2Ba/td> <td align="center">7.32<gydF4y2Ba/td> <td align="center">-2.04<gydF4y2Ba/td> </tr> <tr> <td align="center">1440565 _at<gydF4y2Ba/td> <td align="center">5.79<gydF4y2Ba/td> <td align="center">6.81<gydF4y2Ba/td> <td align="center">-2.04<gydF4y2Ba/td> </tr> <tr> <td align="left">Atp1a2<gydF4y2Ba/td> <td align="center">1443823 _s_at<gydF4y2Ba/td> <td align="center">10.16<gydF4y2Ba/td> <td align="center">11.19<gydF4y2Ba/td> <td align="center">-2.04<gydF4y2Ba/td> </tr> <tr> <td align="left" rowspan="2">Parp8<gydF4y2Ba/td> <td align="center">1442157 _at<gydF4y2Ba/td> <td align="center">4.55<gydF4y2Ba/td> <td align="center">5.58<gydF4y2Ba/td> <td align="center">-2.04<gydF4y2Ba/td> </tr> <tr> <td align="center">1457338 _at<gydF4y2Ba/td> <td align="center">5.27<gydF4y2Ba/td> <td align="center">6.3<gydF4y2Ba/td> <td align="center">-2.04<gydF4y2Ba/td> </tr> <tr> <td align="left">Scn7a<gydF4y2Ba/td> <td align="center">1427495 _at<gydF4y2Ba/td> <td align="center">5.07<gydF4y2Ba/td> <td align="center">6.1<gydF4y2Ba/td> <td align="center">-2.05<gydF4y2Ba/td> </tr> <tr> <td align="left">4833420 g17rik<gydF4y2Ba/td> <td align="center">1419637 _s_at<gydF4y2Ba/td> <td align="center">7.81<gydF4y2Ba/td> <td align="center">8.85<gydF4y2Ba/td> <td align="center">-2.05<gydF4y2Ba/td> </tr> <tr> <td align="left">Rgs12<gydF4y2Ba/td> <td align="center">1429380 _at<gydF4y2Ba/td> <td align="center">6.68<gydF4y2Ba/td> <td align="center">7.71<gydF4y2Ba/td> <td align="center">-2.05<gydF4y2Ba/td> </tr> <tr> <td align="left">Rgs4<gydF4y2Ba/td> <td align="center">1416286 _at<gydF4y2Ba/td> <td align="center">5.76<gydF4y2Ba/td> <td align="center">6.81<gydF4y2Ba/td> <td align="center">-2.07<gydF4y2Ba/td> </tr> <tr> <td align="left">Socs2<gydF4y2Ba/td> <td align="center">1446085 _at<gydF4y2Ba/td> <td align="center">4.48<gydF4y2Ba/td> <td align="center">5.53<gydF4y2Ba/td> <td align="center">-2.07<gydF4y2Ba/td> </tr> <tr> <td align="left">Dlk1<gydF4y2Ba/td> <td align="center">1449939 _s_at<gydF4y2Ba/td> <td align="center">8.7<gydF4y2Ba/td> <td align="center">9.75<gydF4y2Ba/td> <td align="center">-2.07<gydF4y2Ba/td> </tr> <tr> <td align="left" rowspan="2">Kcnj3<gydF4y2Ba/td> <td align="center">1444025 _at<gydF4y2Ba/td> <td align="center">7.85<gydF4y2Ba/td> <td align="center">8.9<gydF4y2Ba/td> <td align="center">-2.07<gydF4y2Ba/td> </tr> <tr> <td align="center">1445659 _at<gydF4y2Ba/td> <td align="center">4.08<gydF4y2Ba/td> <td align="center">5.14<gydF4y2Ba/td> <td align="center">-2.07<gydF4y2Ba/td> </tr> <tr> <td align="left">Ctla2a, Ctla2b<gydF4y2Ba/td> <td align="center">1416811 _s_at<gydF4y2Ba/td> <td align="center">4.16<gydF4y2Ba/td> <td align="center">5.22<gydF4y2Ba/td> <td align="center">-2.08<gydF4y2Ba/td> </tr> <tr> <td align="left">Tm4sf1<gydF4y2Ba/td> <td align="center">1450958 _at<gydF4y2Ba/td> <td align="center">5。6<gydF4y2Ba/td> <td align="center">6.66<gydF4y2Ba/td> <td align="center">-2.08<gydF4y2Ba/td> </tr> <tr> <td align="left" rowspan="2">Ssbp2<gydF4y2Ba/td> <td align="center">1429951 _at<gydF4y2Ba/td> <td align="center">6.91<gydF4y2Ba/td> <td align="center">7.97<gydF4y2Ba/td> <td align="center">-2.09<gydF4y2Ba/td> </tr> <tr> <td align="center">1442609 _at<gydF4y2Ba/td> <td align="center">5.47<gydF4y2Ba/td> <td align="center">6.53<gydF4y2Ba/td> <td align="center">-2.09<gydF4y2Ba/td> </tr> <tr> <td align="left">Gucy1a3<gydF4y2Ba/td> <td align="center">1434141 _at<gydF4y2Ba/td> <td align="center">9.83<gydF4y2Ba/td> <td align="center">10.89<gydF4y2Ba/td> <td align="center">-2.09<gydF4y2Ba/td> </tr> <tr> <td align="left">Cdh11<gydF4y2Ba/td> <td align="center">1450757 _at<gydF4y2Ba/td> <td align="center">8.41<gydF4y2Ba/td> <td align="center">9.47<gydF4y2Ba/td> <td align="center">-2.09<gydF4y2Ba/td> </tr> <tr> <td align="left">Ptn<gydF4y2Ba/td> <td align="center">1448254 _at<gydF4y2Ba/td> <td align="center">8.92<gydF4y2Ba/td> <td align="center">9.99<gydF4y2Ba/td> <td align="center">-2.1<gydF4y2Ba/td> </tr> <tr> <td align="left">Col8a1<gydF4y2Ba/td> <td align="center">1455627 _at<gydF4y2Ba/td> <td align="center">6.76<gydF4y2Ba/td> <td align="center">7.83<gydF4y2Ba/td> <td align="center">-2.1<gydF4y2Ba/td> </tr> <tr> <td align="left">Cdh11<gydF4y2Ba/td> <td align="center">1435120 _at<gydF4y2Ba/td> <td align="center">4.22<gydF4y2Ba/td> <td align="center">5.29<gydF4y2Ba/td> <td align="center">-2.1<gydF4y2Ba/td> </tr> <tr> <td align="left">Socs3<gydF4y2Ba/td> <td align="center">1455899 _x_at<gydF4y2Ba/td> <td align="center">7.92<gydF4y2Ba/td> <td align="center">8.99<gydF4y2Ba/td> <td align="center">-2.11<gydF4y2Ba/td> </tr> <tr> <td align="left">Dpm1<gydF4y2Ba/td> <td align="center">1459961 _a_at<gydF4y2Ba/td> <td align="center">6.05<gydF4y2Ba/td> <td align="center">7.14<gydF4y2Ba/td> <td align="center">-2.12<gydF4y2Ba/td> </tr> <tr> <td align="left">Angpt1<gydF4y2Ba/td> <td align="center">1421441 _at<gydF4y2Ba/td> <td align="center">5.37<gydF4y2Ba/td> <td align="center">6.46<gydF4y2Ba/td> <td align="center">-2.13<gydF4y2Ba/td> </tr> <tr> <td align="left">Col18a1<gydF4y2Ba/td> <td align="center">1426955 _at<gydF4y2Ba/td> <td align="center">8.21<gydF4y2Ba/td> <td align="center">9.3<gydF4y2Ba/td> <td align="center">-2.13<gydF4y2Ba/td> </tr> <tr> <td align="left">Pcdh17<gydF4y2Ba/td> <td align="center">1436920 _at<gydF4y2Ba/td> <td align="center">7.42<gydF4y2Ba/td> <td align="center">8.51<gydF4y2Ba/td> <td align="center">-2.14<gydF4y2Ba/td> </tr> <tr> <td align="left">Figf<gydF4y2Ba/td> <td align="center">1438953 _at<gydF4y2Ba/td> <td align="center">5.95<gydF4y2Ba/td> <td align="center">7.05<gydF4y2Ba/td> <td align="center">-2.14<gydF4y2Ba/td> </tr> <tr> <td align="left">Atp1a2<gydF4y2Ba/td> <td align="center">1434893 _at<gydF4y2Ba/td> <td align="center">8.27<gydF4y2Ba/td> <td align="center">9.37<gydF4y2Ba/td> <td align="center">-2.15<gydF4y2Ba/td> </tr> <tr> <td align="left">Cyr61<gydF4y2Ba/td> <td align="center">1457823 _at<gydF4y2Ba/td> <td align="center">9.73<gydF4y2Ba/td> <td align="center">10.84<gydF4y2Ba/td> <td align="center">-2.15<gydF4y2Ba/td> </tr> <tr> <td align="left">Atp1a2<gydF4y2Ba/td> <td align="center">1427465 _at<gydF4y2Ba/td> <td align="center">9.12<gydF4y2Ba/td> <td align="center">10.23<gydF4y2Ba/td> <td align="center">-2.15<gydF4y2Ba/td> </tr> <tr> <td align="left">Kcnip2<gydF4y2Ba/td> <td align="center">1436275 _at<gydF4y2Ba/td> <td align="center">5.85<gydF4y2Ba/td> <td align="center">6.96<gydF4y2Ba/td> <td align="center">-2.16<gydF4y2Ba/td> </tr> <tr> <td align="left">Ano3<gydF4y2Ba/td> <td align="center">1443612 _at<gydF4y2Ba/td> <td align="center">3.87<gydF4y2Ba/td> <td align="center">5<gydF4y2Ba/td> <td align="center">-2.18<gydF4y2Ba/td> </tr> <tr> <td align="left">Batf3<gydF4y2Ba/td> <td align="center">1453076 _at<gydF4y2Ba/td> <td align="center">4所示。8<gydF4y2Ba/td> <td align="center">5.92<gydF4y2Ba/td> <td align="center">-2.18<gydF4y2Ba/td> </tr> <tr> <td align="left">Hmga2<gydF4y2Ba/td> <td align="center">1422851 _at<gydF4y2Ba/td> <td align="center">5。9<gydF4y2Ba/td> <td align="center">7.03<gydF4y2Ba/td> <td align="center">-2.19<gydF4y2Ba/td> </tr> <tr> <td align="left" rowspan="2">Figf<gydF4y2Ba/td> <td align="center">1449528 _at<gydF4y2Ba/td> <td align="center">6.74<gydF4y2Ba/td> <td align="center">7.88<gydF4y2Ba/td> <td align="center">-2.19<gydF4y2Ba/td> </tr> <tr> <td align="center">1443551 _at<gydF4y2Ba/td> <td align="center">7.19<gydF4y2Ba/td> <td align="center">8.32<gydF4y2Ba/td> <td align="center">-2.19<gydF4y2Ba/td> </tr> <tr> <td align="left">Bgn<gydF4y2Ba/td> <td align="center">1448323 _a_at<gydF4y2Ba/td> <td align="center">6.99<gydF4y2Ba/td> <td align="center">8.13<gydF4y2Ba/td> <td align="center">-2.2<gydF4y2Ba/td> </tr> <tr> <td align="left">Adamts5<gydF4y2Ba/td> <td align="center">1422561 _at<gydF4y2Ba/td> <td align="center">6.06<gydF4y2Ba/td> <td align="center">7.2<gydF4y2Ba/td> <td align="center">-2.2<gydF4y2Ba/td> </tr> <tr> <td align="left">Scn7a<gydF4y2Ba/td> <td align="center">1436044 _at<gydF4y2Ba/td> <td align="center">8<gydF4y2Ba/td> <td align="center">9.14<gydF4y2Ba/td> <td align="center">-2.21<gydF4y2Ba/td> </tr> <tr> <td align="left">Olfm1<gydF4y2Ba/td> <td align="center">1425784 _a_at<gydF4y2Ba/td> <td align="center">7.02<gydF4y2Ba/td> <td align="center">8.16<gydF4y2Ba/td> <td align="center">-2.21<gydF4y2Ba/td> </tr> <tr> <td align="left">Rufy3<gydF4y2Ba/td> <td align="center">1442786 _s_at<gydF4y2Ba/td> <td align="center">3.92<gydF4y2Ba/td> <td align="center">5.08<gydF4y2Ba/td> <td align="center">-2.23<gydF4y2Ba/td> </tr> <tr> <td align="left">Cyr61<gydF4y2Ba/td> <td align="center">1442340 _x_at<gydF4y2Ba/td> <td align="center">10.04<gydF4y2Ba/td> <td align="center">11.21<gydF4y2Ba/td> <td align="center">-2.24<gydF4y2Ba/td> </tr> <tr> <td align="left">Gucy1a3<gydF4y2Ba/td> <td align="center">1420534 _at<gydF4y2Ba/td> <td align="center">7.06<gydF4y2Ba/td> <td align="center">8.22<gydF4y2Ba/td> <td align="center">-2.24<gydF4y2Ba/td> </tr> <tr> <td align="left">Junb<gydF4y2Ba/td> <td align="center">1415899 _at<gydF4y2Ba/td> <td align="center">9.02<gydF4y2Ba/td> <td align="center">10.19<gydF4y2Ba/td> <td align="center">-2.25<gydF4y2Ba/td> </tr> <tr> <td align="left">Zfp36<gydF4y2Ba/td> <td align="center">1452519 _a_at<gydF4y2Ba/td> <td align="center">8.69<gydF4y2Ba/td> <td align="center">9.87<gydF4y2Ba/td> <td align="center">-2.26<gydF4y2Ba/td> </tr> <tr> <td align="left">Fbln5<gydF4y2Ba/td> <td align="center">1416164 _at<gydF4y2Ba/td> <td align="center">6.08<gydF4y2Ba/td> <td align="center">7.25<gydF4y2Ba/td> <td align="center">-2.26<gydF4y2Ba/td> </tr> <tr> <td align="left">Kctd12<gydF4y2Ba/td> <td align="center">1434881 _s_at<gydF4y2Ba/td> <td align="center">6.48<gydF4y2Ba/td> <td align="center">7.66<gydF4y2Ba/td> <td align="center">-2.27<gydF4y2Ba/td> </tr> <tr> <td align="left">Cdc14a<gydF4y2Ba/td> <td align="center">1436913 _at<gydF4y2Ba/td> <td align="center">4所示。4<gydF4y2Ba/td> <td align="center">5.59<gydF4y2Ba/td> <td align="center">-2.28<gydF4y2Ba/td> </tr> <tr> <td align="left">中行<gydF4y2Ba/td> <td align="center">1426869 _at<gydF4y2Ba/td> <td align="center">5.77<gydF4y2Ba/td> <td align="center">6.98<gydF4y2Ba/td> <td align="center">-2.31<gydF4y2Ba/td> </tr> <tr> <td align="left">Fam155a<gydF4y2Ba/td> <td align="center">1435138 _at<gydF4y2Ba/td> <td align="center">5.08<gydF4y2Ba/td> <td align="center">6.29<gydF4y2Ba/td> <td align="center">-2.31<gydF4y2Ba/td> </tr> <tr> <td align="left">Frem1<gydF4y2Ba/td> <td align="center">1455280 _at<gydF4y2Ba/td> <td align="center">5.83<gydF4y2Ba/td> <td align="center">7.07<gydF4y2Ba/td> <td align="center">-2.36<gydF4y2Ba/td> </tr> <tr> <td align="left">04。9月<gydF4y2Ba/td> <td align="center">1448729 _a_at<gydF4y2Ba/td> <td align="center">7.54<gydF4y2Ba/td> <td align="center">8.78<gydF4y2Ba/td> <td align="center">-2.36<gydF4y2Ba/td> </tr> <tr> <td align="left">Ramp1<gydF4y2Ba/td> <td align="center">1431413 _at<gydF4y2Ba/td> <td align="center">6.08<gydF4y2Ba/td> <td align="center">7.32<gydF4y2Ba/td> <td align="center">-2.37<gydF4y2Ba/td> </tr> <tr> <td align="left">Bgn<gydF4y2Ba/td> <td align="center">1416405 _at<gydF4y2Ba/td> <td align="center">7.65<gydF4y2Ba/td> <td align="center">8.89<gydF4y2Ba/td> <td align="center">-2.37<gydF4y2Ba/td> </tr> <tr> <td align="left">Asb14<gydF4y2Ba/td> <td align="center">1449547 _at<gydF4y2Ba/td> <td align="center">4.13<gydF4y2Ba/td> <td align="center">5.38<gydF4y2Ba/td> <td align="center">-2.38<gydF4y2Ba/td> </tr> <tr> <td align="left">液态氧<gydF4y2Ba/td> <td align="center">1448228 _at<gydF4y2Ba/td> <td align="center">7.07<gydF4y2Ba/td> <td align="center">8.34<gydF4y2Ba/td> <td align="center">-2.41<gydF4y2Ba/td> </tr> <tr> <td align="left" rowspan="3">Socs3<gydF4y2Ba/td> <td align="center">1456212 _x_at<gydF4y2Ba/td> <td align="center">7.34<gydF4y2Ba/td> <td align="center">8.61<gydF4y2Ba/td> <td align="center">-2.42<gydF4y2Ba/td> </tr> <tr> <td align="center">1442813 _at<gydF4y2Ba/td> <td align="center">4.08<gydF4y2Ba/td> <td align="center">5.36<gydF4y2Ba/td> <td align="center">-2.42<gydF4y2Ba/td> </tr> <tr> <td align="center">1439535 _at<gydF4y2Ba/td> <td align="center">7.43<gydF4y2Ba/td> <td align="center">8.71<gydF4y2Ba/td> <td align="center">-2.42<gydF4y2Ba/td> </tr> <tr> <td align="left">Cpne5<gydF4y2Ba/td> <td align="center">1442166 _at<gydF4y2Ba/td> <td align="center">9.85<gydF4y2Ba/td> <td align="center">11.13<gydF4y2Ba/td> <td align="center">-2.42<gydF4y2Ba/td> </tr> <tr> <td align="left">Edil3<gydF4y2Ba/td> <td align="center">1433474 _at<gydF4y2Ba/td> <td align="center">4.25<gydF4y2Ba/td> <td align="center">5.52<gydF4y2Ba/td> <td align="center">-2.43<gydF4y2Ba/td> </tr> <tr> <td align="left">Iigp1<gydF4y2Ba/td> <td align="center">1419043 _a_at<gydF4y2Ba/td> <td align="center">6.02<gydF4y2Ba/td> <td align="center">7.3<gydF4y2Ba/td> <td align="center">-2.43<gydF4y2Ba/td> </tr> <tr> <td align="left">Map3k8<gydF4y2Ba/td> <td align="center">1419208 _at<gydF4y2Ba/td> <td align="center">6.58<gydF4y2Ba/td> <td align="center">7.89<gydF4y2Ba/td> <td align="center">-2.48<gydF4y2Ba/td> </tr> <tr> <td align="left">Col8a1<gydF4y2Ba/td> <td align="center">1418440 _at<gydF4y2Ba/td> <td align="center">5.65<gydF4y2Ba/td> <td align="center">6.99<gydF4y2Ba/td> <td align="center">-2.53<gydF4y2Ba/td> </tr> <tr> <td align="left">Clca1;Clca3a1<gydF4y2Ba/td> <td align="center">1417852 _x_at<gydF4y2Ba/td> <td align="center">5.53<gydF4y2Ba/td> <td align="center">6.87<gydF4y2Ba/td> <td align="center">-2.53<gydF4y2Ba/td> </tr> <tr> <td align="left">Igfbp2<gydF4y2Ba/td> <td align="center">1454159 _a_at<gydF4y2Ba/td> <td align="center">5.81<gydF4y2Ba/td> <td align="center">7.18<gydF4y2Ba/td> <td align="center">-2.59<gydF4y2Ba/td> </tr> <tr> <td align="left">Asb15<gydF4y2Ba/td> <td align="center">1439836 _at<gydF4y2Ba/td> <td align="center">3.86<gydF4y2Ba/td> <td align="center">5.24<gydF4y2Ba/td> <td align="center">-2.61<gydF4y2Ba/td> </tr> <tr> <td align="left">04。9月<gydF4y2Ba/td> <td align="center">1455422 _x_at<gydF4y2Ba/td> <td align="center">6.53<gydF4y2Ba/td> <td align="center">7.94<gydF4y2Ba/td> <td align="center">-2.65<gydF4y2Ba/td> </tr> <tr> <td align="left">Vgll3<gydF4y2Ba/td> <td align="center">1453593 _at<gydF4y2Ba/td> <td align="center">4.36<gydF4y2Ba/td> <td align="center">5.78<gydF4y2Ba/td> <td align="center">-2.68<gydF4y2Ba/td> </tr> <tr> <td align="left">Ccdc187<gydF4y2Ba/td> <td align="center">1439194 _at<gydF4y2Ba/td> <td align="center">5.83<gydF4y2Ba/td> <td align="center">7.26<gydF4y2Ba/td> <td align="center">-2.68<gydF4y2Ba/td> </tr> <tr> <td align="left" rowspan="2">Skiv2l2<gydF4y2Ba/td> <td align="center">1447517 _at<gydF4y2Ba/td> <td align="center">4.13<gydF4y2Ba/td> <td align="center">5.56<gydF4y2Ba/td> <td align="center">-2.69<gydF4y2Ba/td> </tr> <tr> <td align="center">1445655 _at<gydF4y2Ba/td> <td align="center">5.35<gydF4y2Ba/td> <td align="center">6.83<gydF4y2Ba/td> <td align="center">-2.79<gydF4y2Ba/td> </tr> <tr> <td align="left">Figf<gydF4y2Ba/td> <td align="center">1438954 _x_at<gydF4y2Ba/td> <td align="center">5.54<gydF4y2Ba/td> <td align="center">7.03<gydF4y2Ba/td> <td align="center">-2.81<gydF4y2Ba/td> </tr> <tr> <td align="left">Olfm1<gydF4y2Ba/td> <td align="center">1455796 _x_at<gydF4y2Ba/td> <td align="center">3.97<gydF4y2Ba/td> <td align="center">5.47<gydF4y2Ba/td> <td align="center">-2.81<gydF4y2Ba/td> </tr> <tr> <td align="left">Egr2<gydF4y2Ba/td> <td align="center">1427683 _at<gydF4y2Ba/td> <td align="center">5。5<gydF4y2Ba/td> <td align="center">6.99<gydF4y2Ba/td> <td align="center">-2.82<gydF4y2Ba/td> </tr> <tr> <td align="left">Ppp1r17<gydF4y2Ba/td> <td align="center">1449240 _at<gydF4y2Ba/td> <td align="center">5.16<gydF4y2Ba/td> <td align="center">6.66<gydF4y2Ba/td> <td align="center">-2.84<gydF4y2Ba/td> </tr> <tr> <td align="left">Pdgfrb<gydF4y2Ba/td> <td align="center">1436970 _a_at<gydF4y2Ba/td> <td align="center">4.57<gydF4y2Ba/td> <td align="center">6.12<gydF4y2Ba/td> <td align="center">-2.93<gydF4y2Ba/td> </tr> <tr> <td align="left">亮度<gydF4y2Ba/td> <td align="center">1423607 _at<gydF4y2Ba/td> <td align="center">6.4<gydF4y2Ba/td> <td align="center">7.98<gydF4y2Ba/td> <td align="center">-2.99<gydF4y2Ba/td> </tr> <tr> <td align="left">弧<gydF4y2Ba/td> <td align="center">1418687 _at<gydF4y2Ba/td> <td align="center">5.94<gydF4y2Ba/td> <td align="center">7.57<gydF4y2Ba/td> <td align="center">-3.1<gydF4y2Ba/td> </tr> <tr> <td align="left">Cntn2<gydF4y2Ba/td> <td align="center">1435165 _at<gydF4y2Ba/td> <td align="center">6.09<gydF4y2Ba/td> <td align="center">7.75<gydF4y2Ba/td> <td align="center">-3.16<gydF4y2Ba/td> </tr> <tr> <td align="left">液态氧<gydF4y2Ba/td> <td align="center">1416121 _at<gydF4y2Ba/td> <td align="center">7.48<gydF4y2Ba/td> <td align="center">9.15<gydF4y2Ba/td> <td align="center">-3.19<gydF4y2Ba/td> </tr> <tr> <td align="left">Col3a1<gydF4y2Ba/td> <td align="center">1427884 _at<gydF4y2Ba/td> <td align="center">5.98<gydF4y2Ba/td> <td align="center">7.71<gydF4y2Ba/td> <td align="center">-3.32<gydF4y2Ba/td> </tr> <tr> <td align="left">Egr2<gydF4y2Ba/td> <td align="center">1427682 _a_at<gydF4y2Ba/td> <td align="center">5.44<gydF4y2Ba/td> <td align="center">7.26<gydF4y2Ba/td> <td align="center">-3.52<gydF4y2Ba/td> </tr> <tr> <td align="left">Sfrp5<gydF4y2Ba/td> <td align="center">1436075 _at<gydF4y2Ba/td> <td align="center">6.34<gydF4y2Ba/td> <td align="center">8.24<gydF4y2Ba/td> <td align="center">-3.75<gydF4y2Ba/td> </tr> <tr> <td align="left">Pcdh17<gydF4y2Ba/td> <td align="center">1453070 _at<gydF4y2Ba/td> <td align="center">6.1<gydF4y2Ba/td> <td align="center">8.01<gydF4y2Ba/td> <td align="center">-3.77<gydF4y2Ba/td> </tr> <tr> <td align="left">Unc80<gydF4y2Ba/td> <td align="center">1434989 _at<gydF4y2Ba/td> <td align="center">5.54<gydF4y2Ba/td> <td align="center">7.75<gydF4y2Ba/td> <td align="center">-4.64<gydF4y2Ba/td> </tr> <tr> <td align="left">Egr3<gydF4y2Ba/td> <td align="center">1436329 _at<gydF4y2Ba/td> <td align="center">3.84<gydF4y2Ba/td> <td align="center">7.06<gydF4y2Ba/td> <td align="center">-9.27<gydF4y2Ba/td> </tr> </tbody> </table> </table-wrap> <fig-group id="fig1"> <label>图1<gydF4y2Ba/label> <p>整理iPS-CM的表征。在100年的存在iPS-CM被培养<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M (PE)去氧肾上腺素诱导肥大。(一)散点图的基因微阵列数据显示log2成绩单iPS-CM和iPS-CM PE治疗之间的关系。(b)前30名,表达下调基因PE-treated iPS-CM。额外的显著调节基因在肥厚性细胞生长所反映出的虚线广场。(c)<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>基因表达被实时PCR验证。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 5<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。Nor1 (d)免疫印迹分析(<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M12"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 8<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>),规范化GAPDH的表达水平。磷酸化的表达一种蛋白激酶(pAkt<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M13"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 8<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)和磷酸化Erk(活跃,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M14"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 4<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>)在整理iPS-CM规范化的磷酸化形式。(e) iPS-CM被播种在fibronectin-coated盖玻片,100处理<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M PE 24 h。细胞进一步固定和孵化Alexa萤石555 phalloidin染色细胞内f -肌动蛋白(红色)。核与DAPI复染色(蓝色),量化显微镜下细胞区域。酒吧:100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>m;<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M15"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 7<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M16"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M17"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Ba/p> <fig id="fig1a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.001a"></graphic> </fig> <fig id="fig1b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.001b"></graphic> </fig> <fig id="fig1c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.001c"></graphic> </fig> <fig id="fig1d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.001d"></graphic> </fig> <fig id="fig1e"> <label>(e)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.001e"></graphic> </fig> </fig-group> </sec> <sec id="sec3.2"> <title>3.2。Nor1表达和Akt激活是强制性的iPS-CM PE-Induced肥大<gydF4y2Ba/title> <p>证明如果<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>表达和Akt激活对肥厚性细胞生长很重要,我们压制<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>表达和Akt活动利用gene-specific siRNA或pI3激酶抑制剂渥曼青霉素,分别(图<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S1a-b<gydF4y2Ba/xref>),治疗前与体育的细胞。肥厚性细胞生长不可能在没有Nor1(图中被观察到<gydF4y2Baxref rid="fig2a" ref-type="fig"> 2(一个)<gydF4y2Ba/xref>)以及抑制Akt的活动(图<gydF4y2Baxref rid="fig2b" ref-type="fig"> 2 (b)<gydF4y2Ba/xref>)表明<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>所需和Akt激活肥大iPS-CM感应。不影响细胞的生存观察(数据没有显示)。<gydF4y2Ba/p> <fig-group id="fig2"> <label>图2<gydF4y2Ba/label> <p>抑制Nor1和Akt活动防止肥大iPS-CM感应。(一)iPS-CM被播种在fibronectin-coated盖玻片和转染Nor1核或控制核,分别。24小时后,细胞被进一步处理PE (100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米)诱导肥大。iPS-CM组织学染色细胞大小量化的f -肌动蛋白(红色)。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M18"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 4<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。(b) iPS-CM服用渥曼青霉素(400海里)之前由PE肥大感应。细胞大小量化由肌动蛋白细胞骨架染色。代表图像进行描述。酒吧:100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>m。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M19"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 4<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。n。=不显著;<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M20"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M21"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Ba/p> <fig id="fig2a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.002a"></graphic> </fig> <fig id="fig2b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.002b"></graphic> </fig> </fig-group> </sec> <sec id="sec3.3"> <title>3.3。检查参与组成分泌腺的msc诱导肥大回归的PE-Treated iPS-CM<gydF4y2Ba/title> <p>刺激骨骨髓来源与干扰素- msc<gydF4y2Baitalic> γ<gydF4y2Ba/italic>和il - 1<gydF4y2Baitalic> β<gydF4y2Ba/italic>伴随着的激活增加NF -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B以及可见的,但不显著,增加细胞内HIF-1<gydF4y2Baitalic> α<gydF4y2Ba/italic>水平(图<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S2a-b<gydF4y2Ba/xref>)。NF -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B代表主要的转录因子控制<gydF4y2Baitalic> 伊诺<gydF4y2Ba/italic>表达对il - 1的回应<gydF4y2Baitalic> β<gydF4y2Ba/italic>刺激,亚硝酸盐水平量化文化上层清液验证msc预处理[<gydF4y2Baxref ref-type="bibr" rid="B20"> 20.<gydF4y2Ba/xref>]。激活NF -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B通常会导致upregulation基因参与细胞凋亡、炎症和细胞粘附等(<gydF4y2Baxref ref-type="bibr" rid="B25"> 25<gydF4y2Ba/xref>]。进一步查明预处理msc (acMSCs)影响iPS-CM肥大,PE-treated iPS-CM的先决条件是cocultured msc使用transwell系统,防止直接和信息交互。细胞面积iPS-CM coculture后显著降低了预处理msc、和类似的结果MSC-conditioned介质(图中补充后20%<gydF4y2Baxref ref-type="fig" rid="fig3a"> 3(一个)<gydF4y2Ba/xref>)。值得注意的是,检查参与组成分泌腺的观察效果MSC对肥大细胞被发现存在剂量依赖的相关性为中等补充条件培养基为10%或更少并没有导致肥大回归(图<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S3<gydF4y2Ba/xref>)。这些结果表明,肥大的回归是由MSC-derived溶性因素。值得注意的是,肥大回归Nor1蛋白质的差别,对这些基因的表达在iPS-CM(图<gydF4y2Baxref ref-type="fig" rid="fig3b"> 3 (b)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> <fig-group id="fig3"> <label>图3<gydF4y2Ba/label> <p>在iPS-CM MSC-derived可溶性介质诱导肥大回归。骨骨髓来源msc刺激了30 ng / ml IFN -<gydF4y2Baitalic> γ<gydF4y2Ba/italic>和3 ng / ml il - 1<gydF4y2Baitalic> β<gydF4y2Ba/italic>24 h。预先处理,msc (acMSCS)与过度增大的间接cocultured iPS-CM。在一些实验中,过分生长iPS-CM培养在培养基补充MSC-conditioned介质(CM)为20%。(一)细胞面积量化iPS-CM是由immunofluorescent染色。代表图像显示。酒吧:100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>m。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M22"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 6<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。(b) Nor1 iPS-CM蛋白表达。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M23"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 5<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M24"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M25"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M26"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Ba/p> <fig id="fig3a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.003a"></graphic> </fig> <fig id="fig3b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.003b"></graphic> </fig> </fig-group> <p>我们下一个旨在识别MSC-derived分子参与肥大的回归。为此,我们进行了微阵列分析封闭基因受干扰素-<gydF4y2Baitalic> γ<gydF4y2Ba/italic>和il - 1<gydF4y2Baitalic> β<gydF4y2Ba/italic>。共有2026个不同的调节基因被确定;其中,1037是调节和989年下调(数据<gydF4y2Baxref ref-type="fig" rid="fig4a"> 4(一)<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref ref-type="fig" rid="fig4c"> 4 (c)<gydF4y2Ba/xref>)。前100名的列表显著调节基因(> 2倍;< 2倍变化)在表<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S1<gydF4y2Ba/xref>。除了许多趋化因子基因编码,<gydF4y2Baitalic> 伊诺<gydF4y2Ba/italic>和<gydF4y2Baitalic> il - 6<gydF4y2Ba/italic>排名前30名的调节基因(图<gydF4y2Baxref ref-type="fig" rid="fig4b"> 4 (b)<gydF4y2Ba/xref>),支持MSC激活和免疫调节因子的表达。基因本体论(去)富集分析Metascape被用来调节基因网络的分类预处理msc(图<gydF4y2Baxref ref-type="fig" rid="fig4c"> 4 (c)<gydF4y2Ba/xref>)。结果表明所确定的基因主要参与细胞反应β干扰素,移行细胞,细胞因子生产,cytokine-mediated信号通路。此外,一些基因的参与凋亡通路的调节,调节dna结合转录因子的活动,和骨髓白细胞激活。<gydF4y2Ba/p> <fig-group id="fig4"> <label>图4<gydF4y2Ba/label> <p>微阵列分析强调差异表达基因的先决条件在msc。(a)的热图代表基因表达在msc和预处理。(b)的前30名,在msc预处理后基因表达下调。(c)浓缩预先处理分析调节基因在msc。<gydF4y2Ba/p> <fig id="fig4a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.004a"></graphic> </fig> <fig id="fig4b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.004b"></graphic> </fig> <fig id="fig4c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.004c"></graphic> </fig> </fig-group> <p>进一步确定MSC-derived分子可能参与肥大回归,将上层清液的预处理msc集中和分级利用Vivaspin离心设备的分子量截止30 kDa, 50 kDa, 100 kDa。集中和滤液,含有小分子,被用来探索对整理iPS-CM的影响。组织学分析显示,所有集中用于实验显著逆转iPS-CM肥大。反过来,在滤液处理细胞保护作用明显降低(图<gydF4y2Baxref rid="fig5a" ref-type="fig"> 5(一个)<gydF4y2Ba/xref>)。<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>表达iPS-CM表现出良好的相关性与细胞区域与分数包含当细胞治疗<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M27"> <mml:mtext> 分子<gydF4y2Ba/mml:mtext> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 30.<gydF4y2Ba/mml:mn> <mml:mtext> </mml:mtext> <mml:mtext> kDa<gydF4y2Ba/mml:mtext> </mml:math> </inline-formula>(30 kDa滤液)和相应的集中,即蛋白质表达的差异没有显著改变(图<gydF4y2Baxref rid="fig4b" ref-type="fig"> 4 (b)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> <fig-group id="fig5"> <label>图5<gydF4y2Ba/label> <p>肥大iPS-CM回归是由可溶性因子大于30 kDa。文化的上层清液预处理msc被超滤分级用列30 kDa, 50 kDa, 100 kDa截止。过分生长iPS-CM服用不同的集中和相应的滤液24 h。MSC-conditioned介质(CM)被用作控制。(一)量化免疫荧光细胞的表面积。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M28"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 10<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。Nor1基因(b)和蛋白质(c)表达在iPS-CM量化。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M29"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 5<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M30"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M31"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Ba/p> <fig id="fig5a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.005a"></graphic> </fig> <fig id="fig5b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.005b"></graphic> </fig> <fig id="fig5c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.005c"></graphic> </fig> </fig-group> </sec> <sec id="sec3.4"> <title>3.4。VEGF分泌的预先处理这些msc逆转肥厚PE-Treated iPS-CM,会使Nor1基因表达<gydF4y2Ba/title> <p>VEGF分泌骨骨髓来源msc是最近报道逆转肥厚性细胞生长<gydF4y2Baxref ref-type="bibr" rid="B26"> 26<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B27"> 27<gydF4y2Ba/xref>]。有发现分子参与减少肥大似乎大于30 kDa,我们下一个决心,如果事先已经msc代表VEGF的潜在来源。重大upregulation的5.8倍<gydF4y2Baitalic> Vegfa<gydF4y2Ba/italic>表达MSC预处理后可以检测到微阵列分析(数据未显示)。VEGF水平明显升高的上层清液预处理msc 24小时和48小时后细胞因子刺激。此外,VEGF是所有超滤浓缩(图中发现<gydF4y2Baxref rid="fig6a" ref-type="fig"> 6(一)<gydF4y2Ba/xref>),以前发现诱导肥大回归iPS-CM(图<gydF4y2Baxref rid="fig5a" ref-type="fig"> 5(一个)<gydF4y2Ba/xref>)。MSC-conditioned介质抗心肌肥厚的影响以及含有介质的零头<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M32"> <mml:mtext> 分子<gydF4y2Ba/mml:mtext> <mml:mo> ><gydF4y2Ba/mml:mo> <mml:mn> 30.<gydF4y2Ba/mml:mn> <mml:mtext> </mml:mtext> <mml:mtext> kDa<gydF4y2Ba/mml:mtext> </mml:math> </inline-formula>强烈降低VEGF失活后VEGF-neutralizing抗体(图<gydF4y2Baxref rid="fig6b" ref-type="fig"> 6 (b)<gydF4y2Ba/xref>)。VEGF中和MSC-conditioned中增加<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>iPS-CM表达式,虽然显著增加Nor1蛋白质含量不能检测到(图<gydF4y2Baxref rid="fig6c" ref-type="fig"> 6 (c)<gydF4y2Ba/xref>)。<gydF4y2Ba/p> <fig-group id="fig6"> <label>图6<gydF4y2Ba/label> <p>MSC-derived VEGF在iPS-CM肥大回归至关重要。(a) VEGF在文化上层的量化与30 ng / ml IFN - msc刺激<gydF4y2Baitalic> γ<gydF4y2Ba/italic>和3 ng / ml il - 1<gydF4y2Baitalic> β<gydF4y2Ba/italic>24 h和那些无血清培养系统的额外的24小时(48小时)。此外,VEGF水平分级MSC-conditioned介质(集中和滤液)ELISA测定。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M33"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 5<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。(b) PE-treated过分生长iPS-CM MSC-conditioned培养基培养的20% (CM) 24 h。控制,细胞培养在培养基补充> 30 kDa集中。VEGF中和、50 ng / ml或150 ng / ml抗VEGF中和抗体是添加到培养基中。细胞表面积被f -肌动蛋白染色量化。代表图像显示。酒吧:100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>m。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M34"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 5<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。(c) Nor1基因和蛋白表达在iPS-CM讲究的量化与VEGF-neutralizing MSC-CM补充抗体的存在。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M35"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 4<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。(d)在肥大细胞内VEGF水平量化iPS-CM培养CM 24 h的20%。msc与未经预处理作为控制。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M36"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 4<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。(e) VEGF水平量化在文化的上层清液PE-treated iPS-CM培养在CM中补充20% 24 h。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M37"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 6<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M38"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M39"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M40"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> p<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。<gydF4y2Ba/p> <fig id="fig6a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.006a"></graphic> </fig> <fig id="fig6b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.006b"></graphic> </fig> <fig id="fig6c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.006c"></graphic> </fig> <fig id="fig6d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.006d"></graphic> </fig> <fig id="fig6e"> <label>(e)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.fig.006e"></graphic> </fig> </fig-group> <p>这些结果不排除这种可能性,VEGF可能来自整理iPS-CM本身,我们进一步测试如果VEGF表达iPS-CM成为受MSC-conditioned介质。如图<gydF4y2Baxref ref-type="fig" rid="fig6d"> 6 (d)<gydF4y2Ba/xref>,可以检测到细胞内VEGF蛋白在msc和iPS-CM;但是,没有在iPS-CM MSC-conditioned介质对VEGF表达的影响可以观察到。此外,无论是PE治疗还是文化MSC-conditioned介质的存在引起了由iPS-CM VEGF分泌增加(图<gydF4y2Baxref ref-type="fig" rid="fig6e"> 6 (e)<gydF4y2Ba/xref>的先决条件),这表明msc代表VEGF的主要来源。<gydF4y2Ba/p> </sec> </sec> <sec id="sec4"> <title>4所示。讨论<gydF4y2Ba/title> <p>在这项研究中,我们首次展示,Nor1代表一个重要分子iPS-CM肥大感应。进一步,我们的数据表明,VEGF分泌预处理小鼠骨骨髓来源iPS-CM msc是有效减少肥大。VEGF-mediated肥大与减少回归强烈相关<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>基因的表达。因此,交付MSC-conditioned介质以及内在的镇压<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>策略表达式可能代表合适,无细胞逆转心脏肥大。<gydF4y2Ba/p> <p>在这项研究中,我们建立了一个<gydF4y2Baitalic> 在体外<gydF4y2Ba/italic>心脏肥大模型小鼠iPS-CM的基础上。刺激细胞肥厚性物质PE增加细胞大小和诱导的重要upregulation核受体<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>。然而,其他关键的upregulation肥大基因<gydF4y2Baitalic> Nppa<gydF4y2Ba/italic>(曾帮工,心房利钠因子),<gydF4y2Baitalic> Nppb<gydF4y2Ba/italic>脑利钠肽(BNP),<gydF4y2Baitalic> Gja1<gydF4y2Ba/italic>(联接蛋白43)<gydF4y2Baitalic> Myh7<gydF4y2Ba/italic>(<gydF4y2Baitalic> β<gydF4y2Ba/italic>肌凝蛋白重链)弱得多,这表明<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>代表了最可行的肥大iPS-CM标记。一些报道认为Nor1参与心脏肥大,心脏衰竭的病理生理学,尽管很少有人了解底层的分子机制。Nor1击倒的报道,以防止isoprenaline-induced在大鼠心肌细胞肥大,而Nor1过度恶化心脏肥大<gydF4y2Baitalic> 在体外<gydF4y2Ba/italic>和<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>(<gydF4y2Baxref ref-type="bibr" rid="B9"> 9<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B10"> 10<gydF4y2Ba/xref>]。在这方面,假设Nor1上调肥大标记和另外的表达促进PARP-1激活,导致功能障碍和心脏肥大,心脏衰竭的进展<gydF4y2Baxref ref-type="bibr" rid="B9"> 9<gydF4y2Ba/xref>]。虽然我们没有调查的机制在iPS-CM Nor1调节肥大,我们发现,沉默的<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>表达式由核完全抑制肥大感应pI3K抑制剂渥曼青霉素以类似的方式。因此,<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>表达式以及pI3K / Akt激活是肥厚性细胞生长的基础虽然额外因素的介入可以预期。<gydF4y2Ba/p> <p>在过去的十年里,msc被认为代表一个最有前途的细胞治疗心血管疾病由于他们长期的方式自我更新能力和分化成不同的专门的细胞类型的能力。此外,有大量的证据表明,msc分泌多种生物活性分子如生长因子、趋化因子、细胞因子(<gydF4y2Baxref ref-type="bibr" rid="B28"> 28<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>msc预处理,大大提高了他们的增殖,分泌,迁移能力和区分的能力(<gydF4y2Baxref ref-type="bibr" rid="B22"> 22<gydF4y2Ba/xref>]。这里,我们目前的数据来源于msc的预先处理证明骨以及MSC-conditioned媒介促进iPS-CM肥大回归表明这种效果是完全依赖于可溶性介质。重要的是,最初的实验表明,msc没有预处理不间接coculture后导致iPS-CM肥大回归。干扰素- MSC预处理<gydF4y2Baitalic> γ<gydF4y2Ba/italic>和il - 1<gydF4y2Baitalic> β<gydF4y2Ba/italic>导致重大upregulation NF -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B,因此诱导upregulation超过1000个基因,他们中的大多数编码趋化因子和细胞因子。因此,il - 1<gydF4y2Baitalic> β<gydF4y2Ba/italic>和干扰素-<gydF4y2Baitalic> γ<gydF4y2Ba/italic>据报道促进NF -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B-dependent HIF-1积累<gydF4y2Baitalic> α<gydF4y2Ba/italic>在常氧条件下(<gydF4y2Baxref ref-type="bibr" rid="B29"> 29日<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B30"> 30.<gydF4y2Ba/xref>]。当我们进一步发现这些分子的分子量似乎大于30 kDa,我们进一步得出结论,大部分的调节趋化因子(分子量~ 10 kDa)可以排除作为保护作用的介质。事实上,许多因素如CCL-2 CCL-3, CCL-5,其基因表达的先决条件是高度增加msc、患者被报道是调节结构重构包括肥大和充血性心脏病(<gydF4y2Baxref ref-type="bibr" rid="B31"> 31日<gydF4y2Ba/xref>]。此外,它曾被发现HIF-1荣格等人<gydF4y2Baitalic> α<gydF4y2Ba/italic>参与调节VEGF通过路径依赖NF -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B (<gydF4y2Baxref ref-type="bibr" rid="B29"> 29日<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>VEGF在心脏肥大的作用是有争议的是讨论。一方面,VEGF是证明开心脏肥大(<gydF4y2Baxref ref-type="bibr" rid="B32"> 32<gydF4y2Ba/xref>),另一方面,VEGF-mediated肥大回归在很大程度上归因于它能够增加心脏血管生成(<gydF4y2Baxref ref-type="bibr" rid="B33"> 33<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B34"> 34<gydF4y2Ba/xref>]。尽管msc产生显著的VEGF (<gydF4y2Baxref ref-type="bibr" rid="B26"> 26<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B35"> 35<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B36"> 36<gydF4y2Ba/xref>),VEGF分泌显著调节MSC预处理。所有集中MSC-conditioned介质包含VEGF在iPS-CM逆转肥厚,表明VEGF诱导肥大回归。然而,应该注意的是,VEGF被确认在所有集中虽然集中器与不同的短裤被用于这项研究。这些结果可以解释为蛋白质的吸光度膜或塑料表面的装置。的基础上生成的结果,我们不能排除其它MSC-derived可溶性分子可能施加antihypertrophic协同或添加剂与VEGF的交互影响。<gydF4y2Ba/p> <p>VEGF中和减毒MSC-conditioned介质的保护作用,以及upregulation<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>可以发现在同一时间。此外,我们的数据不支持蔡等人的研究结果描述了协同增加细胞外后VEGF coculturing肥大心肌细胞和骨骨髓来源msc (<gydF4y2Baxref ref-type="bibr" rid="B26"> 26<gydF4y2Ba/xref>]。细胞内VEGF在iPS-CM upregulation和增加VEGF分泌检测治疗后细胞与MSC-conditioned介质或间接coculture后,分别。这些观察结果表明,预处理msc似乎代表了主要来源供抑制VEGF进而逆转肥厚<gydF4y2Baitalic> Nor1<gydF4y2Ba/italic>在心肌细胞表达。<gydF4y2Ba/p> <p>在这方面,在促进新血管的形成,VEGF另外一直描述诱导巨噬细胞M1转向一个平方米表型(<gydF4y2Baxref ref-type="bibr" rid="B37"> 37<gydF4y2Ba/xref>和减弱心脏肥大<gydF4y2Baxref ref-type="bibr" rid="B26"> 26<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B38"> 38<gydF4y2Ba/xref>]。因此,VEGF的有利影响<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>预计将歧管包括直接antihypertrophic影响心肌细胞,巨噬细胞transpolarization为抗炎表型(<gydF4y2Baxref ref-type="bibr" rid="B37"> 37<gydF4y2Ba/xref>),和血管生成<gydF4y2Baxref ref-type="bibr" rid="B33"> 33<gydF4y2Ba/xref>]。根据这些结果,细胞因子预处理应该考虑一个工具来增加骨骨髓来源msc的治疗效果。<gydF4y2Ba/p> <p>然而,在目前的研究有一定的局限性,需要解决。首先,我们的研究是有限的使用成人骨骨髓来源msc减少自我更新和分化能力,高不同批次之间的差异,和进步的细胞衰老<gydF4y2Baxref ref-type="bibr" rid="B39"> 39<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref ref-type="bibr" rid="B41"> 41<gydF4y2Ba/xref>]。第二,检查参与组成分泌腺的msc似乎也显著不同,根据主人的年龄,健康状况,壁龛细胞所在。此外,NF -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>以前曾有报道称,B是至关重要的细胞因子和生长因子的分泌,msc、和一些研究提出,基因改造的msc可以提高NK -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B信号和旁分泌活动(<gydF4y2Baxref ref-type="bibr" rid="B42"> 42<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B43"> 43<gydF4y2Ba/xref>]。尽管我们为NF -提供了证据<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B活化预处理msc、NF -<gydF4y2Baitalic> κ<gydF4y2Ba/italic>B激活可能显著不同MSC制剂之间的不同。进一步,我们没有考虑检查参与组成分泌腺MSC的复杂性包括微泡,小分子核糖核酸,液,和线粒体转移等<gydF4y2Baxref ref-type="bibr" rid="B44"> 44<gydF4y2Ba/xref>]。限制可能很大程度上忽略了更有吸引力的发展策略的基础上,“诱导多能性”细胞衍生msc。这些细胞被证明有更高的增殖能力,较高的端粒酶活性,细胞衰老低于骨骨髓来源msc使一代的高度同质的人群没有损失质量功能(<gydF4y2Baxref ref-type="bibr" rid="B39"> 39<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B45"> 45<gydF4y2Ba/xref>]。<gydF4y2Ba/p> <p>总之,我们的研究结果表明,从干扰素-条件培养基<gydF4y2Baitalic> γ<gydF4y2Ba/italic>- - - il - 1<gydF4y2Baitalic> β<gydF4y2Ba/italic>刺激msc可能代表一个适当的治疗方法治疗LVH。然而,还需要进一步的研究来描述预先处理这些iPS细胞衍生msc和检查参与组成分泌腺的有效性和安全性评估组件用于治疗心脏肥大<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>。<gydF4y2Ba/p> </sec> <sec id="sec5"> <title>5。结论<gydF4y2Ba/title> <p>预处理与il - 1骨骨髓来源msc<gydF4y2Baitalic> β<gydF4y2Ba/italic>和干扰素-<gydF4y2Baitalic> γ<gydF4y2Ba/italic>大力提高旁分泌的行动。此外,VEGF分泌msc逆转Nor1-dependent iPS-CM肥大。,交付MSC-conditioned介质可能代表一个有前途的治疗方法治疗游离LVH虽然<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>疗效需要进一步调查。<gydF4y2Ba/p> </sec> <back> <sec sec-type="data-availability"> <title>数据可用性<gydF4y2Ba/title> <p>数据集支持本文的结论可以从相应的作者在合理的请求。<gydF4y2Ba/p> </sec> <sec sec-type="COI-statement"> <title>的利益冲突<gydF4y2Ba/title> <p>作者宣称没有利益冲突。<gydF4y2Ba/p> </sec> <sec> <title>作者的贡献<gydF4y2Ba/title> <p>丹尼斯·菲利普和米歇尔Holthaus贡献同样这项工作。<gydF4y2Ba/p> </sec> <ack> <title>确认<gydF4y2Ba/title> <p>我们感谢纳塔莉亚Mierau, Sabine施密特和艾伦Veit优秀的技术援助。本研究在一定程度上支持德国心脏研究基金会的资助(A.P.G.和t。w。,# F / 06/16)和德国研究基金会的资助(陷入)。<gydF4y2Ba/p> </ack> <sec sec-type="supplementary-material" id="supplementary-material-1"> <title>补充材料<gydF4y2Ba/title> <supplementary-material xlink:href="//www.newsama.com/downloads/journals/sci/2021/8888575.f1.zip" id="supp-1" mimetype="application/zip"> 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