ISL1 overexpression enhances the survival of transplanted human mesenchymal stem cells in a murine myocardial infarction model.
ISL1 overexpression enhances the survival of transplanted human mesenchymal stem cells in a murine myocardial infarction model.
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ISL1过表达可增强小鼠心肌梗死模型中移植的人间充质干细胞的存活率
DOI：
10.1186/s13287-018-0803-7
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发表时间：
2018-02-26
影响因子：
7.5
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Xiang Q;Liao Y;Chao H;Huang W;Liu J;Chen H;Hong D;Zou Z;Xiang AP;Li W
背景LIM-homeobox转录因子islet-1（ISL 1）已被提议作为心血管祖细胞的标志物。本研究旨在探讨在人间充质干细胞（human mesenchymal stem cells，hMSCs）中强制表达ISL 1是否能改善心肌梗死（myocardial infarction，MI）的治疗效果。采用流式细胞术、免疫荧光、Western blotting、TUNEL法和RNA测序等方法对ISL 1-hMSCs（ISL 1-hMSCs）的功能进行评价。与对照hMSCs或磷酸盐缓冲盐水相比，用ISL 1-hMSCs治疗4周后MI后心脏的左心室射血分数和缩短分数更大。我们还发现，ISL 1过表达增加血管生成，减少细胞凋亡和炎症。ISL 1-hMSCs的更大潜力可能归因于移植后存活细胞数量的增加。ISL 1-hMSCs条件培养液可降低H2 O2对心肌细胞株H9 c2的凋亡作用。为了阐明这一发现的分子基础，我们采用RNA测序来比较对照hMSCs和ISL 1-hMSCs的造血相关基因表达谱。结果显示胰岛素样生长因子结合蛋白3（insulin-like growth factor binding protein 3，IGFBP 3）是ISL 1-hMSCs中唯一RPKM值大于100的基因，且ISL 1-hMSCs与对照hMSCs的差异倍数变化大于3，提示IGFBP 3可能通过旁分泌作用在ISL 1-hMSCs的抗凋亡作用中发挥重要作用。此外，IGFBP 3在来自ISL 1-hMSC的条件培养基中的表达几乎是来自对照hMSC的条件培养基中的表达的四倍。此外，IGFBP 3中和抗体逆转了ISL 1-hMSCs-CM.ConclusionsThese结果表明，ISL 1在hMSCs中的过表达促进细胞存活在MI模型中，并增强其旁分泌功能，以保护心肌细胞，这可能是通过IGFBP 3介导的。ISL 1在hMSCs中的过表达可能代表了一种新的策略，用于增强MI后干细胞治疗的有效性。
BackgroundThe LIM-homeobox transcription factor islet-1 (ISL1) has been proposed as a marker for cardiovascular progenitor cells. This study investigated whether forced expression of ISL1 in human mesenchymal stem cells (hMSCs) improves myocardial infarction (MI) treatment outcomes.MethodsThe lentiviral vector containing the human elongation factor 1α promoter, which drives the expression of ISL1 (EF1α-ISL1), was constructed using the Multisite Gateway System and used to transduce hMSCs. Flow cytometry, immunofluorescence, Western blotting, TUNEL assay, and RNA sequencing were performed to evaluate the function of ISL1-overexpressing hMSCs (ISL1-hMSCs).ResultsThe in vivo results showed that transplantation of ISL1-hMSCs improved cardiac function in a rat model of MI. Left ventricle ejection fraction and fractional shortening were greater in post-MI hearts after 4 weeks of treatment with ISL1-hMSCs compared with control hMSCs or phosphate-buffered saline. We also found that ISL1 overexpression increased angiogenesis and decreased apoptosis and inflammation. The greater potential of ISL1-hMSCs may be attributable to an increased number of surviving cells after transplantation. Conditioned medium from ISL1-hMSCs decreased the apoptotic effect of H2O2on the cardiomyocyte cell line H9c2. To clarify the molecular basis of this finding, we employed RNA sequencing to compare the apoptotic-related gene expression profiles of control hMSCs and ISL1-hMSCs. The results showed that insulin-like growth factor binding protein 3 (IGFBP3) was the only gene in ISL1-hMSCs with a RPKM value higher than 100 and that the difference fold-change between ISL1-hMSCs and control hMSCs was greater than 3, suggesting that IGFBP3 might play an important role in the anti-apoptosis effect of ISL1-hMSCs through paracrine effects. Furthermore, the expression of IGFBP3 in the conditioned medium from ISL1-hMSCs was almost fourfold greater than that in conditioned medium from control hMSCs. Moreover, the IGFBP3 neutralization antibody reversed the apoptotic effect of ISL1-hMSCs-CM.ConclusionsThese results suggest that overexpression of ISL1 in hMSCs promotes cell survival in a model of MI and enhances their paracrine function to protect cardiomyocytes, which may be mediated through IGFBP3. ISL1 overexpression in hMSCs may represent a novel strategy for enhancing the effectiveness of stem cell therapy after MI.
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影响因子：
4.6
作者：
Kazezian Z;Gawri R;Haglund L;Ouellet J;Mwale F;Tarrant F;O'Gaora P;Pandit A;Alini M;Grad S
通讯作者：
Grad S
影响因子：
120.7
作者：
Heldman, Alan W.;DiFede, Darcy L.;Fishman, Joel E.;Zambrano, Juan P.;Trachtenberg, Barry H.;Karantalis, Vasileios;Mushtaq, Muzammil;Williams, Adam R.;Suncion, Viky Y.;McNiece, Ian K.;Ghersin, Eduard;Soto, Victor;Lopera, Gustavo;Miki, Roberto;Willens, Howard;Hendel, Robert;Mitrani, Raul;Pattany, Pradip;Feigenbaum, Gary;Oskouei, Behzad;Byrnes, John;Lowery, Maureen H.;Sierra, Julio;Pujol, Mariesty V.;Delgado, Cindy;Gonzalez, Phillip J.;Rodriguez, Jose E.;Bagno, Luiza Lima;Rouy, Didier;Altman, Peter;Foo, Cheryl Wong Po;da Silva, Jose;Anderson, Erica;Schwarz, Richard;Mendizabal, Adam;Hare, Joshua M.
通讯作者：
Hare, Joshua M.
影响因子：
46.9
作者：
Lane, Steven W.;Williams, David A.;Watt, Fiona M.
通讯作者：
Watt, Fiona M.
影响因子：
64.8
作者：
Laugwitz, KL;Moretti, A;Chien, KR
通讯作者：
Chien, KR
影响因子：
5.2
作者：
Gnecchi, Massimiliano;He, Huamei;Melo, Luis G.;Noiseaux, Nicolas;Morello, Fulvio;de Boer, Rudolf A.;Zhang, Lunan;Pratt, Richard E.;Dzau, Victor J.;Ingwall, Joanne S.
通讯作者：
Ingwall, Joanne S.