Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration
Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration
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DOI：
10.1016/j.jconrel.2013.10.034
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发表时间：
2014-01-10
影响因子：
10.8
通讯作者：
Blanco-Prieto, Maria J.
中科院分区：
文献类型：
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作者：
Formiga, Fabio R.;Pelacho, Beatriz;Blanco-Prieto, Maria J.
酸性成纤维细胞生长因子(FGF1)和神经调节蛋白-1(NRG1)是参与心脏发育和再生的生长因子。微粒子(MPS)介导细胞因子的持续释放，可用于克服全身给药过程中治疗蛋白稳定性有限的问题。我们试图检查含有FGF1和NRG1的微粒(MPS)是否可以促进心肌梗死(MI)大鼠模型的心脏再生。我们调查了这种疗法有益效果的可能潜在机制，特别是那些与内源性再生有关的机制。采用复乳化溶剂挥发法制备了FGF1和NRG1负载的MPS。73只雌性SD大鼠永久结扎冠状动脉前降支，4天后在梗死区心肌内注射MPS。在治疗后1周和3个月评估心功能、心脏组织重塑、血运重建、细胞凋亡、心肌细胞增殖和干细胞归巢。MPS能有效包裹FGF1和NRG1，持续释放生物活性蛋白。治疗三个月后，在接受生长因子负载MPS(FGF1、NRG1或FGF1/NRG1)治疗的大鼠中，检测到心功能有统计学上的显著改善。该疗法抑制了心脏重构，使心肌梗死面积变小，纤维化程度降低，并诱导组织血运重建。检测心肌细胞增殖和祖细胞募集情况。我们的数据支持NRG1和FGF1与蛋白质输送系统结合用于心脏再生的治疗益处。这种方法可以扩大到临床前和临床研究中使用。(C)2013爱思唯尔B.V.保留所有权利。
Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment were detected. Our data support the therapeutic benefit ofNRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies. (C) 2013 Elsevier B.V. All rights reserved.