Exosomes derived from human umbilical cord MSCs rejuvenate aged MSCs and enhance their functions for myocardial repair

Abstract

Background: Age and other cardiovascular risk factors have been reported to impair the activities of mesenchymal stem cells (MSCs), which will affect the efficacy of stem cell transplantation. The objective of the study is to investigate whether exosomes derived from human umbilical cord MSCs (UMSCs) could enhance the activities of bone marrow MSCs from old person (OMSCs), and improve their capacity for cardiac repair. Methods: Exosomes extracted from conditioned medium of UMSCs were used to treat OMSCs to generate OMSCs Exo. The key molecule in the exosomes that have potential to rejuvenate aged MSCs were screened, and the role of OMSC was tested in the mouse model of mycardial infarction (MI). Results: We found the activity of senescence-associated β-galactosidase and the expression of aging-related factors such as p53, p21, and p16 were significantly higher in OMSCs than those in UMSCs. After treatment with UMSC exosomes, these senescence phenotypes of OMSCs were remarkably reduced. The proliferation, migration, differentiation, and anti-apoptotic and paracrine effect were increased in OMSCs Exo. In vivo study, mice with cardiac infarction had significantly better cardiac function, less fibrosis, and more angiogenesis after they were injected with OMSCs Exo as compared with those with OMSC. There was more miR-136 expression in UMSCs and OMSCs Exo than in OMSCs. Upregulation of miR-136 by transfection of miR-136 mimic into OMSCs significantly attenuated the apoptosis and senescence of OMSCs. Apoptotic peptidase activating factor (Apaf1) was found to be the downstream gene that is negatively regulated by miR-136 via directly targeting at its 3′UTR. Conclusion: Our data suggest that exosomes from young MSCs can improve activities of aged MSCs and enhance their function for myocardial repair by transferring exosomal miR-136 and downregulating Apaf1.

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

“…The therapeutic effect of UMSC EVs also involved targeting of the Bim apoptosis gene by exosomal miR-24 while immune rejection of BM-MSC used for cell-based therapy was prevented and cardiac repair was enhanced by knockout of human leucocyte antigen light chain β2 microglobulin to modulate exosome imprinting [ 184 ]. In a mouse MI model, the therapeutic properties of BM-MSC from elderly human donors was improved by pretreating the cells with EVs from UMSC, which resulted in the loss of senescence and apoptosis from the BM-MSC and their prolonged survival in vivo resulting in improved cardiac function, increased cardiac vessel density, and decreased scar [ 197 ]. This improved outcome was attributed to the effect of EV miR-136, which inhibited expression of apoptotic peptidase activating factor [ 197 ].…”

“…In a mouse MI model, the therapeutic properties of BM-MSC from elderly human donors was improved by pretreating the cells with EVs from UMSC, which resulted in the loss of senescence and apoptosis from the BM-MSC and their prolonged survival in vivo resulting in improved cardiac function, increased cardiac vessel density, and decreased scar [ 197 ]. This improved outcome was attributed to the effect of EV miR-136, which inhibited expression of apoptotic peptidase activating factor [ 197 ]. In type 2 diabetes mellitus stroke mice, administration of exosomes from human umbilical cord blood derived stem cells improved cardiac function, increased myocardial vascularization, and decreased cardiomyocyte hypertrophy, oxidative stress, interstitial fibrosis and expression of TGF-β [ 198 ].…”

Exosomes Secreted by Nucleus Pulposus Stem Cells Derived From Degenerative Intervertebral Disc Exacerbate Annulus Fibrosus Cell Degradation via Let-7b-5p

“…miRNAs, important intermediaries of the exosome function, play an important role in maintaining normal homeostasis ( Shan et al, 2019 ). Exosomes transport miRNAs to recipient cells and participate in such physiological processes as cell proliferation, differentiation, migration, and apoptosis ( Zhang et al, 2020 ). To further explore how D-NPSC-exo affects AFCs, N-NPSC-exo and D-NPSC-exo were sequenced and found to be discrepant in some miRNAs.…”

Role of miRNA-324-5p-Modified Adipose-Derived Stem Cells in Post-Myocardial Infarction Repair

“…Stem cells are known to secrete various factors that have paracrine activities; they home to hypoxic and/or inflamed areas, and release trophic factors that hasten endogenous repair and the secreted bioactive factors limit local immune system, enhance angiogenesis, inhibit fibrosis and apoptosis, and stimulate differentiation of tissue-residing stem cells ( 65 ). Once transplanted into a damaged organ, MSCs release paracrine factors that nurture the injured area, prevent further adverse cardiac remodeling, and mediate tissue repair along with vasculature ( 66 - 68 ). We will focus on whether miR-324-5p is carried into cardiomyocytes by ADSCs through paracrine effect in the next research.…”