Davis Michael E, Hsieh Patrick C H, Takahashi Tomosaburo, Song Qing, Zhang Shuguang, Kamm Roger D, Grodzinsky Alan J, Anversa Piero, Lee Richard T
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02139, USA.
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8155-60. doi: 10.1073/pnas.0602877103. Epub 2006 May 12.
Strategies for cardiac repair include injection of cells, but these approaches have been hampered by poor cell engraftment, survival, and differentiation. To address these shortcomings for the purpose of improving cardiac function after injury, we designed self-assembling peptide nanofibers for prolonged delivery of insulin-like growth factor 1 (IGF-1), a cardiomyocyte growth and differentiation factor, to the myocardium, using a "biotin sandwich" approach. Biotinylated IGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated self-assembling peptides. This biotin sandwich strategy allowed binding of IGF-1 but did not prevent self-assembly of the peptides into nanofibers within the myocardium. IGF-1 that was bound to peptide nanofibers activated Akt, decreased activation of caspase-3, and increased expression of cardiac troponin I in cardiomyocytes. After injection into rat myocardium, biotinylated nanofibers provided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in vivo increased activation of Akt in the myocardium. When combined with transplanted cardiomyocytes, IGF-1 delivery by biotinylated nanofibers decreased caspase-3 cleavage by 28% and increased the myocyte cross-sectional area by 25% compared with cells embedded within nanofibers alone or with untethered IGF-1. Finally, cell therapy with IGF-1 delivery by biotinylated nanofibers improved systolic function after experimental myocardial infarction, demonstrating how engineering the local cellular microenvironment can improve cell therapy.
心脏修复策略包括细胞注射，但这些方法因细胞植入、存活和分化不佳而受到阻碍。为了解决这些缺点以改善损伤后的心脏功能，我们设计了自组装肽纳米纤维，采用“生物素夹心”方法将心肌细胞生长和分化因子胰岛素样生长因子1（IGF-1）长期递送至心肌。生物素化的IGF-1与四价链霉亲和素复合，然后与生物素化的自组装肽结合。这种生物素夹心策略允许IGF-1结合，但不阻止肽在心肌内自组装成纳米纤维。与肽纳米纤维结合的IGF-1激活了Akt，降低了caspase-3的激活，并增加了心肌细胞中心肌肌钙蛋白I的表达。注入大鼠心肌后，生物素化纳米纤维提供了28天的持续IGF-1递送，并且在体内靶向递送IGF-1增加了心肌中Akt的激活。与单独嵌入纳米纤维中的细胞或与未连接的IGF-1相比，当与移植的心肌细胞联合使用时，通过生物素化纳米纤维递送IGF-1可使caspase-3裂解减少28%，并使心肌细胞横截面积增加25%。最后，通过生物素化纳米纤维递送IGF-1的细胞疗法改善了实验性心肌梗死后的收缩功能，证明了工程化局部细胞微环境如何改善细胞疗法。
