Comparative study of hypoxic and normoxic preconditioned mesenchymal stem cell derived extracellular vesicles and their therapeutic implications

Munshi, Afnan M N Alam; Rigg, Emma; Mehic, Jelica; Rosu‐Myles, Michael; Lavoie, Jessie R.

doi:10.1016/j.jcyt.2018.02.052

Cited by 2 publications

(1 citation statement)

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“…The idea of hypoxia preconditioning of ADSCs came from remote ischemic preconditioning (RIPC), which is a novel method where ischemia followed by reperfusion of one organ is believed to protect remote organs either due to release of biochemical messengers in the circulation or activation of nerve pathways, resulting in release of messengers that have a protective effect[ 32 ]. With regard to the underlying mechanism of RIPC in cardioprotection, whether such preconditioning efficacy may extended application in vitro to provide a promising treatment by using EVs generated by ADSCs exposure to hypoxia preconditioning[ 33 ]. For example, EVs generated by HP MSCs were adapted to improve traumatic spinal cord injury via its paracrine mechanisms and unfolded a myocardium preservation effect against ischemia-reperfusion injury[ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells alleviates myocardial injury by targeting thioredoxin-interacting protein-mediated hypoxia-inducible factor-1α pathway

Mao¹,

Zhang²,

Li³

et al. 2022

WJSC

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BACKGROUND Extracellular vesicles (EVs) derived from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) have better cardioprotective effects against myocardial infarction (MI) in the early stage than EVs isolated from normoxic (NC)-MSCs. However, the cardioprotective mechanisms of HP-EVs are not fully understood. AIM To explore the cardioprotective mechanism of EVs derived from HP MSCs. METHODS We evaluated the cardioprotective effects of HP-EVs or NC-EVs from mouse adipose-derived MSCs (ADSCs) following hypoxia in vitro or MI in vivo , in order to improve the survival of cardiomyocytes (CMs) and restore cardiac function. The degree of CM apoptosis in each group was assessed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/PI assays. MicroRNA (miRNA) sequencing was used to investigate the functional RNA diversity between HP-EVs and NC-EVs from mouse ADSCs. The molecular mechanism of EVs in mediating thioredoxin-interacting protein (TXNIP) was verified by the dual-luciferase reporter assay. Co-immunoprecipitation, western blotting, and immunofluorescence were performed to determine if TXNIP is involved in hypoxia-inducible factor-1 alpha (HIF-1α) ubiquitination and degradation via the chromosomal region maintenance-1 (CRM-1)-dependent nuclear transport pathway. RESULTS HP-EVs derived from MSCs reduced both infarct size (necrosis area) and apoptotic degree to a greater extent than NC-EVs from CMs subjected to hypoxia in vitro and mice with MI in vivo . Sequencing of EV-associated miRNAs showed the upregulation of 10 miRNAs predicted to bind TXNIP, an oxidative stress-associated protein. We showed miRNA224-5p, the most upregulated miRNA in HP-EVs, directly combined the 3’ untranslated region of TXNIP and demonstrated its critical protective role against hypoxia-mediated CM injury. Our results demonstrated that MI triggered TXNIP-mediated HIF-1α ubiquitination and degradation in the CRM-1-mediated nuclear transport pathway in CMs, which led to aggravated injury and hypoxia tolerance in CMs in the early stage of MI. CONCLUSION The anti-apoptotic effects of HP-EVs in alleviating MI and the hypoxic conditions of CMs until reperfusion therapy may partly result from EV miR-224-5p targeting TXNIP.

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