Exosomes Engineered to Express a Cardiomyocyte Binding Peptide Demonstrate Improved Cardiac Retention in Vivo
Exosomes Engineered to Express a Cardiomyocyte Binding Peptide Demonstrate Improved Cardiac Retention in Vivo
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DOI：
10.1038/s41598-019-46407-1
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发表时间：
2019-07-11
影响因子：
4.6
通讯作者：
Lang, Jennifer K.
中科院分区：
文献类型：
--
作者：
Mentkowski, Kyle, I;Lang, Jennifer K.
心脏损伤会导致心肌细胞死亡，并可能导致剩余细胞的病理性重塑，从而导致心力衰竭。尽管新药和小分子具有治疗潜力，但在以细胞特异性方式有效传递心脏保护剂的能力方面仍存在差距，同时将非特异性传递到其他器官的可能性降至最低。心脏球源性细胞(CDCs)来源的外切体能刺激血管生成，诱导内源性心肌细胞增殖，调节心肌细胞的凋亡和肥大。虽然在高剂量下具有天然的心脏保护作用，但未经修饰的CDC-外切体表现出有限的心脏趋向性。为了建立一种能够靶向心肌细胞的高效胞外递送系统，我们通过基因工程使CDCs表达Lamp2b，一种胞外膜蛋白，与心肌细胞特异肽WLSEAGPVVTVRALRGTGSW融合。从工程CDC中分离出的外切体在其表面表达CMP，并保持其固有的物理特性。与非靶向外切体相比，靶向外切体心肌内注射后，心肌细胞摄取增加，心肌细胞凋亡减少，心脏滞留增加。重要的是，我们建立了一种新的靶向系统来改善心肌细胞对胞外体的摄取，并为细胞特异性胞外体递送药物和基因治疗奠定了基础，以改善缺血和非缺血损伤后的心脏功能。
Injury to the heart results in cardiomyocyte cell death and can lead to pathological remodeling of remaining cells, contributing to heart failure. Despite the therapeutic potential of new drugs and small molecules, there remains a gap in the ability to efficiently deliver cardioprotective agents in a cell specific manner while minimizing nonspecific delivery to other organs. Exosomes derived from cardiosphere-derived cells (CDCs) have been shown to stimulate angiogenesis, induce endogenous cardiomyocyte proliferation and modulate cardiomyocyte apoptosis and hypertrophy. While innately cardioprotective at high doses, unmodified CDC-exosomes demonstrate limited cardiac tropism. To generate an efficient exosomal delivery system that can target cardiomyocytes, we engineered CDCs to express Lamp2b, an exosomal membrane protein, fused to a cardiomyocyte specific peptide (CMP), WLSEAGPVVTVRALRGTGSW. Exosomes isolated from engineered CDCs expressed CMP on their surface and retained their native physical properties. Targeted exosomes resulted in increased uptake by cardiomyocytes, decreased cardiomyocyte apoptosis, and higher cardiac retention following intramyocardial injection when compared with non-targeted exosomes. Importantly, we established a novel targeting system to improve exosomal uptake by cardiomyocytes and laid the foundation for cell-specific exosomal delivery of drug and gene therapies to improve the functional capacity of the heart following both ischemic and non-ischemic injury.