LncRNA KLF3-AS1 in human mesenchymal stem cell-derived exosomes ameliorates pyroptosis of cardiomyocytes and myocardial infarction through miR-138-5p/Sirt1 axis

Abstract

AimMyocardial infarction (MI) is a severe disease with increased mortality and disability rates, posing heavy economic burden for society. Exosomes were uncovered to mediate intercellular communication after MI. This study aims to explore the effect and mechanism of lncRNA KLF3-AS1 in exosomes secreted by human mesenchymal stem cells (hMSCs) on pyroptosis of cardiomyocytes and MI.MethodsExosomes from hMSCs were isolated and identified. Exosomes from hMSCs with transfection of KLF3-AS1 for overexpression were injected into MI rat model or incubated with hypoxia cardiomyocytes. Effect of KLF3-AS1 on MI area, cell viability, apoptosis, and pyroptosis was determined. The relationship among miR-138-5p, KLF3-AS1, and Sirt1 was verified by dual-luciferase reporter assay. Normal cardiomyocytes were transfected with miR-138-5p inhibitor or sh-Sirt1 to clarify whether alteration of miR-138-5p or sh-Sirt1 can regulate the effect of KLF3-AS1 on cardiomyocytes.ResultsExosomes from hMSCs were successfully extracted. Transfection of KLF3-AS1 exosome in rats and incubation with KLF3-AS1 exosome in hypoxia cardiomyocytes both verified that overexpression of KLF3-AS1 in exosomes leads to reduced MI area, decreased cell apoptosis and pyroptosis, and attenuated MI progression. KLF3-AS1 can sponge miR-138-5p to regulate Sirt1 expression. miR-138-5p inhibitor transfection and KLF3-AS1 exosome incubation contribute to attenuated pyroptosis and MI both in vivo and in vitro, while transfection of sh-Sirt1 could reverse the protective effect of exosomal KLF3-AS1 on hypoxia cardiomyocytes.ConclusionLncRNA KLF3-AS1 in exosomes secreted from hMSCs by acting as a ceRNA to sponge miR-138-5p can regulate Sirt1 so as to inhibit cell pyroptosis and attenuate MI progression.

Exosomal long non-coding RNA MSTRG.292666.16 is associated with osimertinib (AZD9291) resistance in non-small cell lung cancer

“…siRNA of lncRNA MSTRG.292666.16 and its negative control (NC) were synthesized by Sangon Biotech (Shanghai, China). siRNA-MSTRG292666.16 and si-NC were transfected into H1975 cells by using lipofectamine2000 (Thermo, USA) according to previously described procedure [53].…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Opportunities and Challenges for Clinical Translation

“…Chemical modification of EVs by addition of RGD peptides conjugated onto EV surfaces led the EVs to pass the blood brain barrier and target brain cells after ischemic stroke ( Tian et al, 2018 ). EVs can also be loaded with drugs by cell transfection and genetic expression of a candidate gene, or by drug encapsulation after their isolation [( Mao et al, 2019 ; He et al, 2020 ; Ou et al, 2020 ); for review, see Crivelli et al (2017) ]. MSC-EVs were extensively characterized as drug delivery platform and shown to have greater internalization capabilities than commercial liposomes ( Le Saux et al, 2020 ).…”

Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine

“…In a follow-up study, exosomes from human MSCs transfected with the lncRNA KLF3-AS1 were injected into rats with MI. The overexpression of KLF3-AS1 in exosomes reduced the MI area, apoptosis, and pyroptosis, and attenuated MI progression by acting as a competing endogenous RNA (ceRNA) to sponge miR-138-5p that can regulate Sirt1 so as to suppress cell pyroptosis and attenuate MI progression[ 120 ]. Moreover, human umbilical cord derived MSC-Exos protected cardiomyocytes from AMI injury by transferring miR-19a, targeting SOX6, activating AKT, and inhibiting JNK3/caspase-3 activation[ 121 ].…”