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通过对表达Pim-1激酶的心脏祖细胞进行基因工程改造来增强心肌再生。

Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase.

作者信息

Fischer Kimberlee M, Cottage Christopher T, Wu Weitao, Din Shabana, Gude Natalie A, Avitabile Daniele, Quijada Pearl, Collins Brett L, Fransioli Jenna, Sussman Mark A

机构信息

San Diego State Heart Institute, San Diego State University, San Diego, CA, USA.

出版信息

Circulation. 2009 Nov 24;120(21):2077-87. doi: 10.1161/CIRCULATIONAHA.109.884403. Epub 2009 Nov 9.

DOI:10.1161/CIRCULATIONAHA.109.884403
PMID:19901187
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2787902/
Abstract

BACKGROUND

Despite numerous studies demonstrating the efficacy of cellular adoptive transfer for therapeutic myocardial regeneration, problems remain for donated cells with regard to survival, persistence, engraftment, and long-term benefits. This study redresses these concerns by enhancing the regenerative potential of adoptively transferred cardiac progenitor cells (CPCs) via genetic engineering to overexpress Pim-1, a cardioprotective kinase that enhances cell survival and proliferation.

METHODS AND RESULTS

Intramyocardial injections of CPCs overexpressing Pim-1 were given to infarcted female mice. Animals were monitored over 4, 12, and 32 weeks to assess cardiac function and engraftment of Pim-1 CPCs with echocardiography, in vivo hemodynamics, and confocal imagery. CPCs overexpressing Pim-1 showed increased proliferation and expression of markers consistent with cardiogenic lineage commitment after dexamethasone exposure in vitro. Animals that received CPCs overexpressing Pim-1 also produced greater levels of cellular engraftment, persistence, and functional improvement relative to control CPCs up to 32 weeks after delivery. Salutary effects include reduction of infarct size, greater number of c-kit(+) cells, and increased vasculature in the damaged region.

CONCLUSIONS

Myocardial repair is significantly enhanced by genetic engineering of CPCs with Pim-1 kinase. Ex vivo gene delivery to enhance cellular survival, proliferation, and regeneration may overcome current limitations of stem cell-based therapeutic approaches.

摘要

背景

尽管众多研究证明了细胞过继转移对治疗性心肌再生的有效性，但对于捐赠细胞而言，在存活、持久性、植入及长期益处方面仍存在问题。本研究通过基因工程增强过继转移的心脏祖细胞（CPCs）的再生潜能，使其过度表达Pim-1（一种可增强细胞存活和增殖的心脏保护激酶），从而解决了这些问题。

方法与结果

对梗死的雌性小鼠进行心肌内注射过度表达Pim-1的CPCs。通过超声心动图、体内血流动力学及共聚焦成像对动物进行4周、12周和32周的监测，以评估心脏功能及Pim-1 CPCs的植入情况。在体外给予地塞米松后，过度表达Pim-1的CPCs显示出增殖增加以及与心肌源性谱系定向相关标志物的表达增加。相对于对照CPCs，接受过度表达Pim-1的CPCs的动物在注射后长达32周时，细胞植入、持久性及功能改善水平也更高。有益效果包括梗死面积减小、c-kit(+)细胞数量增加以及受损区域血管生成增加。

结论

利用Pim-1激酶对CPCs进行基因工程可显著增强心肌修复。离体基因传递以增强细胞存活、增殖及再生可能会克服当前基于干细胞治疗方法的局限性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c71/2787902/c57d755d274b/nihms153745f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c71/2787902/c57d755d274b/nihms153745f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c71/2787902/09d7db0a6c9c/nihms153745f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c71/2787902/57d9628ec3a0/nihms153745f2.jpg
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