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 June 3, 2019; First published April 29, 2019
Citation Information: J Clin Invest. 2019;129(6):2237-2250. https://doi.org/10.1172/JCI123135.
View: Text | PDF
Research Article Cardiology Stem cells

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

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

×

Figure 3

Mechanisms of exosome-mediated cardiac repair.

Options: View larger image (or click on image) Download as PowerPoint
Mechanisms of exosome-mediated cardiac repair. (A) Representative images...
(A) Representative images of post-MI heart sections stained with Ki-67 (green), α-SA (red), and DAPI. White boundaries show infarct area, and white arrows indicate Ki-67+ cells in the peri-infarct zone. Scale bar: 10 μm (B) Heart sections stained with vWF (red), α-SA (green) in response to NEXO, FEXO, or PBS treatment. White arrows indicate capillary structures in the peri-infarct zone. Scale bar: 50 μm. (C) Heart sections stained with TUNEL (green), α-SA (red), and DAPI (blue). White arrows indicate apoptotic cardiomyocytes in the peri-infarct zone. Scale bar: 50 μm. (D) Quantification of cycling cardiomyocytes (Ki-67+/α-SA+). (E) Quantification of capillary density (vWF+). (F) Quantification of cardiomyocyte apoptosis (TUNEL+/α-SA+). (D–F) n = 6 animals per group, 3 heart sections for each animal. *P < 0.05, **P < 0.01, ***P < 0.001. One-way ANOVA with Bonferroni post hoc correction. All values are mean ± SD. FEXO, exosomes derived from the cardiac cells of patients with heart failure. NEXO, exosomes derived from the cardiac cells of normal heart donors.