Enhancement of Myocardial Regeneration Through Genetic Engineering of Cardiac Progenitor Cells Expressing Pim-1 Kinase

被引：178

作者：

Fischer, Kimberlee M. ^{[1
]}

Cottage, Christopher T. ^{[1
]}

Wu, Weitao ^{[1
]}

Din, Shabana ^{[1
]}

Gude, Natalie A. ^{[1
]}

Avitabile, Daniele ^{[1
]}

Quijada, Pearl ^{[1
]}

Collins, Brett L. ^{[1
]}

Fransioli, Jenna ^{[1
]}

Sussman, Mark A. ^{[1
]}

机构：

[1] San Diego State Univ, San Diego State Heart Inst, San Diego, CA 92182 USA

来源：

CIRCULATION | 2009年 / 120卷 / 21期

基金：

美国国家卫生研究院;

关键词：

echocardiography; gene therapy; hemodynamics; infarction; SCAFFOLD ATTACHMENT REGION; EMBRYONIC STEM-CELLS; INFARCTED MYOCARDIUM; GROWTH; HEART; MULTIPOTENT; ACTIVATION; PHOSPHORYLATION; INHIBITION; PROTECTION;

D O I：

10.1161/CIRCULATIONAHA.109.884403

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. (Circulation. 2009;120:2077-2087.)

引用

页码：2077 / U45

页数：29

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