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Purification and Transplantation of Myogenic Progenitor Cell Derived Exosomes to Improve Cardiac Function in Duchenne Muscular Dystrophic Mice
Published on: April 10, 2019
Heart-targeting exosomes from human cardiosphere-derived cells improve the therapeutic effect on cardiac hypertrophy
Liang Mao1,2, Yun-Da Li1, Ruo-Lan Chen1
1Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China.
Insights
Modified exosomes from human cardiosphere-derived cells (CDCs) show improved heart targeting for treating cardiac hypertrophy. These engineered exosomes enhance therapeutic effects by inhibiting key signaling pathways involved in heart remodeling.
Area of Science:
- Regenerative Medicine
- Cardiovascular Biology
- Nanotechnology
Background:
- Human cardiosphere-derived cells (CDCs) and their exosomes show therapeutic potential for cardiovascular disorders.
- Current exosome delivery methods are inconvenient for clinical application.
- Myocardial hypertrophy remains a significant challenge in cardiovascular disease treatment.
Purpose of the Study:
- To enhance the therapeutic efficacy of CDC-derived exosomes (EXO) for myocardial hypertrophy.
- To improve exosome delivery and targeting to the heart using a heart homing peptide (HHP).
Main Methods:
- Engineered exosomes (HHP-EXO) displaying a heart homing peptide (HHP) fused to LAMP2b.
- Evaluation of cardiomyocyte-targeting capability and therapeutic effects in mouse models of myocardial hypertrophy (TAC).
- Investigation of molecular mechanisms in angiotensin II-induced neonatal rat cardiomyocyte (NRCM) hypertrophy using biochemical and molecular biology techniques.
Main Results:
- HHP-EXO exhibited enhanced accumulation in mouse hearts and cultured NRCMs compared to control exosomes (CON-EXO).
- Intravenous HHP-EXO administration significantly improved cardiac function and reduced left ventricular hypertrophy in TAC mice.
- HHP-EXO treatment inhibited key hypertrophy markers (β-MHC, BNP) and signaling pathways (STAT3, ERK1/2, AKT) via miRNA-148a and GP130.
Conclusions:
- HHP-modified CDC-exosomes preferentially target the heart, enhancing therapeutic effects against cardiac hypertrophy.
- The mechanism involves miRNA-148a-mediated suppression of GP130, leading to inhibition of the STAT3/ERK1/2/AKT pathway.
- This strategy offers a promising approach for improving exosome-based therapies for cardiovascular diseases.
Abstract:
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 β-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.
