期刊
JOURNAL OF NANOBIOTECHNOLOGY
卷 20, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12951-022-01630-3
关键词
Genetic engineering; Exosomes; Heart homing peptide; Cardiosphere-derived cells; Cardiac hypertrophy
资金
- Central Government for Local Development of Science and Technology of Sichuan Province [2020ZYD047]
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province [xtcx2019-15]
- Southwest Medical University
- National Nature Science Foundation of China [81700268, U1605226]
- Luzhou-Southwest Medical University [2018LZXNYDZK25]
The study demonstrates the potential of heart homing peptide (HHP) displayed exosomes from human cardiosphere-derived cells (CDCs) to enhance the therapeutic effect on myocardial hypertrophy. The HHP-exosomes showed higher accumulation in the heart and improved cardiac function and remodeling in mouse models. This beneficial effect is likely mediated through the miRNA-148a-mediated suppression of GP130 signaling pathway.
Exosomes of human cardiosphere-derived cells (CDCs) are very promising for treating cardiovascular disorders. However, the current challenge is inconvenient delivery methods of exosomes for clinical application. The present study aims to explore the potential to enhance the therapeutic effect of exosome (EXO) from human CDCs to myocardial hypertrophy. A heart homing peptide (HHP) was displayed on the surface of exosomes derived from CDCs that were forced to express the HHP fused on the N-terminus of the lysosomal-associated membrane protein 2b (LAMP2b). The cardiomyocyte-targeting capability of exosomes were analyzed and their therapeutic effects were evaluated in a mouse model of myocardial hypertrophy induced by transverse aorta constriction (TAC). The molecular mechanisms of the therapeutic effects were dissected in angiotensin II-induced neonatal rat cardiomyocyte (NRCMs) hypertrophy model using a combination of biochemistry, immunohistochemistry and molecular biology techniques. We found that HHP-exosomes (HHP-EXO) accumulated more in mouse hearts after intravenous delivery and in cultured NRCMs than control exosomes (CON-EXO). Cardiac function of TAC mice was significantly improved with intravenous HHP-EXO administration. Left ventricular hypertrophy was reduced more by HHP-EXO than CON-EXO via inhibition of beta-MHC, BNP, GP130, p-STAT3, p-ERK1/2, and p-AKT. Similar results were obtained in angiotensin II-induced hypertrophy of NRCMs, in which the beneficial effects of HHP-EXO were abolished by miRNA-148a inhibition. Our results indicate that HHP-EXO preferentially target the heart and improve the therapeutic effect of CDCs-exosomes on cardiac hypertrophy. The beneficial therapeutic effect is most likely attributed to miRNA-148a-mediated suppression of GP130, which in turn inhibits STAT3/ERK1/2/AKT signaling pathway, leading to improved cardiac function and remodeling.
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