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Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies.

ABSTRACT: AimsStem cell-derived extracellular vesicles (EVs) have emerged as a promising therapy for myocardial infarction, but its effects remain incompletely understood. We aim to systematically review the efficacy of EVs on myocardial infarction in both small and large animals.MethodsOn April 5, 2018, we searched the PubMed, Embase and Web of Science databases using variations of "myocardial infarction" and "extracellular vesicle". Controlled studies about the treatment effects of stem cell-derived EVs in myocardial infarction animal model were included. Meta-regression analysis was used to reveal the factors affecting the EVs treatments.ResultsOf 1210 studies retrieved, 24 were eligible for meta-analysis. EVs injection was associated with the improvements of left ventricular ejection fraction (12.65%), fractional shortening (7.54%) and the reduction of infarct size/area at risk (-15.55%). Meta-regression analysis did not reveal the association between treatment efficacy and type of stem cell, ligation-to-injection interval, route of delivery, dosage of delivery or follow-up period (all P values > 0.05). The median quality score of eligible studies was only 1, indicating potential risks of bias.ConclusionStem cell-derived EVs improve cardiac function and reduce infarct size in myocardial infarction animals, but current pool-up study reveals no associations between common factors and treatment effects.

SUBMITTER: Yang L

PROVIDER: S-EPMC6402509 | biostudies-other | 2019 Feb

REPOSITORIES: biostudies-other

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Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies.

Yang Lihong L Zhu Jialu J Zhang Cong C Wang Juntao J Yue Fengyang F Jia Xingtai X Liu Hongzhi H

Aging 20190201 4

<b>Aims</b>Stem cell-derived extracellular vesicles (EVs) have emerged as a promising therapy for myocardial infarction, but its effects remain incompletely understood. We aim to systematically review the efficacy of EVs on myocardial infarction in both small and large animals.<b>Methods</b>On April 5, 2018, we searched the PubMed, Embase and Web of Science databases using variations of "myocardial infarction" and "extracellular vesicle". Controlled studies about the treatment effects of stem ce ...[more]

PMID: 30792374

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Project description:Objective: This study aimed to explore the role of circular RNAs (circRNAs) in M2 macrophage (M2M)-derived small extracellular vesicles (SEVs) in myocardial fibrosis development. Methods: The regulatory role of M2M-derived extracellular vesicles (EVs) was evaluated in a mouse model of acute myocardial infarction. Immunofluorescence, quantitative real-time PCR (RT-qPCR), nanoparticle tracking analysis, Western blot analysis and electron microscopy were used to identify macrophages, large extracellular vesicles (LEVs) and SEVs. The circRNA expression profiles of M0 macrophages (M0Ms) and M2Ms were determined by microarray analysis. Bioinformatic analysis, cell coculture and cell proliferation assays were performed to investigate the expression, function, and regulatory mechanisms of circUbe3a in vitro. qPCR, RNA immunoprecipitation (RIP), dual-luciferase reporter assays, RNA fluorescence in situ hybridization (RNA-FISH), Western blot analysis and a series of rescue experiments were used to verify the correlation among circUbe3a, miR-138-5p and RhoC. Results: CircUbe3a from M2M-derived SEVs triggered functional changes in cardiac fibroblasts (CFs). CircUbe3a was synthesized and loaded into SEVs during increased M2M infiltration after myocardial infarction. The fusion of the released SEVs with the plasma membrane likely caused the release of circUbe3a into the cytosol of CFs. Silencing or overexpressing circUbe3a altered CF proliferation, migration, and phenotypic transformation in vitro. We confirmed that circUbe3a plays a crucial role in enhancing functional changes in CFs by sponging miR-138-5p and then translationally repressing RhoC in vitro. In vivo, the addition of M2M-derived SEVs or overexpression of circUbe3a significantly exacerbated myocardial fibrosis after acute myocardial infarction, and these effects were partially abolished by circUbe3a-specific shRNA. Conclusions: Our findings suggest that M2M-derived circUbe3a-containing SEVs promote the proliferation, migration, and phenotypic transformation of CFs by directly targeting the miR-138-5p/RhoC axis, which may also exacerbate myocardial fibrosis after acute myocardial infarction.

Project description:BackgroundExosomes (EXOs) derived from stem cells have become a potential new treatment for acute myocardial infarction (AMI). However, their impact is still not fully understood. Therefore, we performed this meta-analysis to systematically review the efficacy of EXOs on AMI in preclinical animal models.MethodsWe searched PubMed, EMBASE, and the Web of Science from September 1, 1980 to September 1, 2021, to retrieve the studies reporting the therapeutic effects of EXOs on AMI animal models. Secondary endpoints include the fractional shortening (FS), infarct size (IS), fibrosis area (FA), the TNF-α, IL-6 and IL-10 levels, the apoptosis rate and the number of autophagic vesicles. Two authors independently screened the articles based on inclusion and exclusion criteria. All statistical analyses were conducted using Stata14.0.ResultsTen studies satisfied the inclusion criteria. Pooled analyses demonstrated that the levels of LVEF (WMD = 3.67%; 95% CI 2.28-5.07%; P = 0.000), FS (WMD = 3.69%; 95% CI 2.06-5.33%; P = 0.000), IS (WMD = -4.52%, 95% CI - 7.14 to - 1.9%; P = 0.001), and FA (WMD = -7.04%, 95% CI - 8.74 to - 5.34%; P = 0.000), TNF-α (WMD = -3.09, 95% CI - 5.47 to - 0.72; P = 0.011), TL-6 (WMD = -6.34, 95% CI - 11.2 to - 1.49; P < 0.01), TL-10 (WMD = 6.37, 95% CI 1.53-11.21; P = 0.01), the apoptosis rate (WMD = -8.23, 95% CI - 15.29 to - 1.17; P = 0.000), and the number of autophagic vesicles (WMD = -4.52, 95% CI - 7.43 to - 1.62; P = 0.000). Subgroup analysis showed that the EXOs were derived from HMSCs. Subgroup analysis showed that the EXOs derived from HMSCs, and that exosome therapy immediately after myocardial infarction can better improve the LVEF.ConclusionsEXOs therapy has the potential to improve cardiac function, fibrogenesis, and inflammatory response, as well as reducing cell apoptosis and autophagy in preclinical AMI animal models. This can inform future human clinical trials of EXOs.

Project description:IntroductionExtracellular vesicles from mesenchymal stromal cells (MSC-EVs) have shown promise in wound healing. Their use in diabetic wounds specifically, however, remains pre-clinical and their efficacy remains uncertain less clear. A systematic review of preclinical studies is needed to determine the efficacy of MSC-EVs in the treatment of diabetic wounds to accelerate the clinical translation of this cell-based therapy.MethodsPubMed and Embase were searched (to June 23, 2020). All English-language, full-text, controlled interventional studies comparing MSC-EVs to placebo or a "no treatment" arm in animal models of diabetic wounds were included. Study outcomes, including wound closure (primary outcome), scar width, blood vessel number and density, and re-epithelialisation were pooled using a random effects meta-analysis. Risk of bias (ROB) was assessed using the SYRCLE tool for pre-clinical animal studies.ResultsA total of 313 unique records were identified from our search, with 10 full text articles satisfying inclusion criteria (n = 136 animals). The administration of MSC-EVs improved closure of diabetic wounds compared to controls with a large observed effect (Standardized Mean Difference (SMD) 5.48, 95% Confidence Interval (CI) 3.55-8.13). Healing was further enhanced using MSC-EVs enriched in non-coding RNAs or microRNAs compared to controls (SMD 9.89, 95%CI 7.32-12.46). Other outcomes, such as blood vessel density and number, scar width, and re-epithelialisation were improved with the administration of MSC-EVs, with a large effect. ROB across studies was unclear.ConclusionMSC-EVs, particularly following enrichment for specific RNAs, are a promising treatment for diabetic wounds in pre-clinical studies and translation to the clinical domain appears warranted.RegistrationPROSPERO #CRD42020199327 [248]. Forest plot demonstrating increased wound closure rates of diabetic wounds receiving genetically modified MSC-EVs that were enriched for specific RNAs. DFO = deferoxamine. Control groups were inactive (no treatment or saline) except for 3 studies which used hydrogels without MSC-EVs as control (Li M 2016; Shi 2017; Tao 2016).

Project description:In animal models, human bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EV) have been found to have beneficial effects in cardiovascular disease, but only when administered via intramyocardial injection. The biodistribution of either intravenous or intramyocardial injection of MSC-EV in the presence of myocardial injury is uncharacterized at this time. We hypothesized that intramyocardial injection will ensure delivery of MSC-EV to the ischemic myocardium, while intravenous injection will not. Human bone marrow mesenchymal stem cells were cultured and the MSC-EV were isolated and characterized. The MSC-EVs were then labeled with DiD lipid dye. FVB mice with normal cardiac function underwent left coronary artery ligation followed by either peri-infarct intramyocardial or tail vein injection of 3*106 or 2*109 particles of DiD-labeled MSC-EV or a DiD-saline control. The heart, lungs, liver, spleen and kidneys were harvested 2 h post-injection and were submitted for fluorescent molecular tomography imaging. Myocardial uptake of MSC-EV was only visualized after intramyocardial injection of 2*109 MSC-EV particles (p = 0.01) compared to control, and there were no differences in cardiac fluorescence after tail vein injection of MSC-EV (p = 0.5). There was no significantly detectable MSC-EV uptake in other organs after intramyocardial injection. After tail vein injection of 2*109 particles of MSC-EV, the liver (p = 0.02) and spleen (p = 0.04) appeared to have diffuse MSC-EV uptake compared to controls. Even in the presence of myocardial injury, only intramyocardial but not intravenous administration resulted in detectable levels of MSC-EV in the ischemic myocardium. This study confirms the role for intramyocardial injection in maximal and effective delivery of MSC-EV. Our ongoing studies aimed at developing bioengineered MSC-EV for targeted delivery to the heart may render MSC-EV clinically applicable for cardiovascular disease.

Project description:BackgroundLong Intergenic noncoding RNA predicting CARdiac remodeling (LIPCAR) is a long noncoding RNA identified in plasma of patients after myocardial infarction (MI) to be associated with left ventricle remodeling (LVR). LIPCAR was also shown to be a predictor of early death in heart failure (HF) patients. However, no information regarding the expression of LIPCAR and its function in heart as well as the mechanisms involved in its transport to the circulation is known. The aims of this study are (1) to characterize the transporter of LIPCAR from heart to circulation; (2) to determine whether LIPCAR levels in plasma isolated-extracellular vesicles (EVs) reflect the alteration of its expression in total plasma and could be used as biomarkers of LVR post-MI.MethodsSince expression of LIPCAR is restricted to human species and the limitation of availability of cardiac biopsy samples, serum-free conditioned culture media from HeLa cells were first used to characterize the extracellular transporter of LIPCAR before validation in EVs isolated from human cardiac biopsies (non-failing and ischemic HF patients) and plasma samples (patients who develop or not LVR post-MI). Differential centrifugation at 20,000g and 100,000g were performed to isolate the large (lEVs) and small EVs (sEVs), respectively. Western blot and nanoparticle tracking (NTA) analysis were used to characterize the isolated EVs. qRT-PCR analysis was used to quantify LIPCAR in all samples.ResultsWe showed that LIPCAR is present in both lEVs and sEVs isolated from all samples. The levels of LIPCAR are higher in lEVs compared to sEVs isolated from HeLa conditioned culture media and cardiac biopsies. No difference of LIPCAR expression was observed in tissue or EVs isolated from cardiac biopsies obtained from ischemic HF patients compared to non-failing patients. Interestingly, LIPCAR levels were increased in lEVs and sEVs isolated from MI patients who develop LVR compared to patients who did not develop LVR.ConclusionOur data showed that large EVs are the main extracellular vesicle transporter of LIPCAR from heart into the circulation independently of the status, non-failing or HF, in patients. The levels of LIPCAR in EVs isolated from plasma could be used as biomarkers of LVR in post-MI patients.

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Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies.

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Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies.

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