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microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential
Li Qiao, … , Yongjun Li, Ke Cheng
Li Qiao, … , Yongjun Li, Ke Cheng
Published April 29, 2019
Citation Information: J Clin Invest. 2019;129(6):2237-2250. https://doi.org/10.1172/JCI123135.
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Research Article Cardiology Stem cells

microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential

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Abstract

Exosomes, as functional paracrine units of therapeutic cells, can partially reproduce the reparative properties of their parental cells. The constitution of exosomes, as well as their biological activity, largely depends on the cells that secrete them. We isolated exosomes from explant-derived cardiac stromal cells from patients with heart failure (FEXO) or from normal donor hearts (NEXO) and compared their regenerative activities in vitro and in vivo. Patients in the FEXO group exhibited an impaired ability to promote endothelial tube formation and cardiomyocyte proliferation in vitro. Intramyocardial injection of NEXO resulted in structural and functional improvements in a murine model of acute myocardial infarction. In contrast, FEXO therapy exacerbated cardiac function and left ventricular remodeling. microRNA array and PCR analysis revealed dysregulation of miR-21-5p in FEXO. Restoring miR-21-5p expression rescued FEXO’s reparative function, whereas blunting miR-21-5p expression in NEXO diminished its therapeutic benefits. Further mechanistic studies revealed that miR-21-5p augmented Akt kinase activity through the inhibition of phosphatase and tensin homolog. Taken together, the heart failure pathological condition altered the miR cargos of cardiac-derived exosomes and impaired their regenerative activities. miR-21-5p contributes to exosome-mediated heart repair by enhancing angiogenesis and cardiomyocyte survival through the phosphatase and tensin homolog/Akt pathway.

Authors

Li Qiao, Shiqi Hu, Suyun Liu, Hui Zhang, Hong Ma, Ke Huang, Zhenhua Li, Teng Su, Adam Vandergriff, Junnan Tang, Tyler Allen, Phuong-Uyen Dinh, Jhon Cores, Qi Yin, Yongjun Li, Ke Cheng

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Figure 6

Manipulation of miR21 in exosomes modulates their therapeutic potency.

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Manipulation of miR21 in exosomes modulates their therapeutic potency.
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miR-21-5p–deficient exosomes were produced by transfecting healthy cardiac cells with anti–miR-21-5p oligo (NEXO + anti–miR-21). miR-21-5p–restored exosomes were engineered by transfecting heart failure cardiac cells with miR-21-5p oligo (FEXO + miR-21), followed by media conditioning and exosome isolation, as previously described. Scrambled miR oligo was used as a control (NEXO/FEXO + miR-scr). (A) LVEF was measured by echocardiography 3 weeks after treatment. (B) Treatment effects (changes in LVEF at 3 weeks relative to baseline) were calculated for each group. (C and D) Representative Masson’s trichrome staining of myocardial section 3 weeks after treatments. Scale bar: 1 mm. (E–G) Quantitative analysis of infarct size, infarct wall thickness, and viable tissue from Masson’s trichrome-stained images. n = 6 animals per group. *P < 0.05, **P < 0.01, ***P < 0.001. One-way ANOVA with Bonferroni post hoc correction. All values are mean ± SD.
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