Dataset Information

Therapeutic potential of extracellular vesicles in preclinical stroke models: a systematic review and meta-analysis.

ABSTRACT:

Objectives

Currently there is a paucity of clinically available regenerative therapies for stroke. Extracellular vesicles (EV) have been investigated for their potential as modulators of regeneration in the poststroke brain. This systematic review and meta-analysis aims to provide a summary of the efficacy of therapeutic EVs in preclinical stroke models, to inform future research in this emerging field.

Methods

Studies were identified by a comprehensive literature search of two online sources and subsequent screening. Studies using lesion volume or neurological score as outcome measures were included. Standardised mean difference (SMD) and 95% CIs were calculated using a restricted maximum likelihood random effects model. Publication bias was assessed with Egger's regression and presented as funnel plots with trim and fill analysis. Subgroup analysis was performed to assess the effects of different study variables. Study quality and risk of bias were assessed using the CAMARADES checklist.

Results

A total of 20 publications were included in the systematic review, of which 19 were assessed in the meta-analysis (43 comparisons). Overall, EV interventions improved lesion volume (SMD: -1.95, 95% CI -2.72 to 1.18) and neurological scores (SMD: -1.26, 95% CI -1.64 to 0.87) compared with control groups. Funnel plots were asymmetrical suggesting publication bias, and trim and fill analysis predicted seven missing studies for lesion volume. Subgroup analysis suggested administration at 0-23 hours after stroke was the most effective timepoint for EV treatment. The median score on the CAMARADES checklist was 7 (IQR: 5-8).

Conclusions

EVs may offer a promising new avenue for stroke therapies, as EV-based interventions had positive impacts on lesion volume and neurological score in preclinical stroke models.

Prospero registration number

CRD42019134925.

SUBMITTER: Thomas JM

PROVIDER: S-EPMC8749279 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

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:BACKGROUND:Over the past decade, mesenchymal stromal cells have been increasingly investigated for their therapeutic potential in several different illnesses. However, cell therapy can be limited by potentially serious adverse events including cell embolus formation and tumorigenesis. Importantly, the protective effects of mesenchymal stromal cells are largely mediated by paracrine mechanisms including release of extracellular vesicles. This systematic review intends to synthesize the current knowledge of mesenchymal stromal cell-derived extracellular vesicles as a therapeutic option for preclinical models of disease, inflammation, or injury. METHODS:A systematic literature search of MEDLINE, Embase, and BIOSIS databases will be conducted. Interventional preclinical in vivo studies using extracellular vesicles derived from any tissue source of mesenchymal stromal cells will be included. Studies will be screened by abstract, and full-text by two independent reviewers. Eligible studies will undergo data extraction with subcategorization into domains based on disease. Methods utilized for extracellular vesicle characterization and isolation will be collected, as well as information on interventional traits, such as tissue source of mesenchymal stromal cells, dosage regimen, and vesicle modifications. Reported outcomes will be collected to determine which diseases studied may be impacted most from treatment with mesenchymal stromal cell-derived extracellular vesicles. DISCUSSION:This systematic review will summarize preclinical studies investigating the therapeutic efficacy of both small and large extracellular vesicles derived by mesenchymal stromal cells. Extracellular vesicles represent a possibility to harness the benefits of mesenchymal stromal cells with added benefits of reduced manufacturing costs and an improved safety profile. Hence, there has been an exponential increase in interest for developing this cell-free therapy with hundreds of preclinical studies published to date. However, a vast amount of heterogeneity between groups relates to methods of extracellular vesicle isolation, characterization, and study design. This review will capture this heterogeneity and identify the most commonly used and optimal approaches to evaluate mesenchymal stromal cell-derived extracellular vesicle treatment. A meta-analysis of outcomes within each disease domain will help elucidate which fields of research demonstrate promise for developing extracellular vesicles as a novel cell-free therapy. Summarizing this robust information on extracellular vesicles as an intervention can provide guidance for designing preclinical studies with hopes of future clinical translation.

Project description:Background: Following extensive, positive results in pre-clinical experiments, Bone Marrow Derived-Mesenchymal Stromal Cells (BM-MSCs) are now being tested as a novel therapy for ischemic stroke in ongoing clinical trials. However, multiple critical questions relating to their translational application remain to be clarified. We performed a comprehensive, systematic review and meta-analysis of pre-clinical studies to evaluate the efficacy of BM-MSCs on functional outcomes after ischemic stroke, as well as the independent role of translational factors on their effect size. Methods: We systematically reviewed the literature and identified articles using BM-MSCs in animal models of focal ischemic stroke. After abstraction of all relevant data, we performed a meta-analysis to estimate the combined effect size of behavioral endpoints after BM-MSC administration. To describe the effect size across many behavioral outcomes, we divided these outcomes into four categories: (1) Composite scores, (2) Motor Tests, (3) Sensorimotor Tests, and (4) Cognitive Tests. We also performed a meta-regression analysis for measuring the effect of individual characteristics of BM-MSC administration on the effect size. Results: Our results from 141 articles indicate a significant beneficial effect on composite, motor, and sensorimotor outcomes after treatment with BM-MSCs compared to control groups. We found no major differences in treatment effect based on delivery route, dose, fresh vs. frozen preparation, or passage number. There were no consistent findings supporting a difference in treatment effect based on time windows from acute periods (0-6 h) vs. later windows (2-7 days). Furthermore, these positive treatment effects on functional outcome were consistent across different labs in different parts of the world as well as over the last 18 years. There was a negative correlation between publication year and impact factor. Conclusions: Our results show worldwide efficacy of BM-MSCs in improving functional outcomes in pre-clinical animal models of stroke and support testing these cells in clinical trials in various ranges of time windows using different delivery routes. The continued growing number of publications showing functional benefit of BM-MSCs are now adding limited value to an oversaturated literature spanning 18 years. Researchers should focus on identifying definitive mechanisms on how BM-MSCs lead to benefit in stroke models.

Project description:INTRODUCTION:Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating neurologic condition with high mortality rates and long-term complications for surviving infants. Mesenchymal stem/stromal cells (MSCs) have emerged as novel therapeutic agents with promising results in experimental studies of HIE. The purpose of this study is to (a) methodically review the current preclinical literature describing MSC therapy in animal models of HIE, (b) quantify the effect size in regards to functional neurologic outcome, and (c) identify research gaps/limitations that should be addressed prior to future preclinical and clinical studies. METHODS:Adhering to the Systematic Review Protocol for Animal Intervention Studies, a systematic search of English articles was performed. Eligible studies were identified and data regarding study characteristics and outcome measures was extracted. After quality assessment, meta-analysis and meta-regression were performed to generate random effect size using standardized mean difference (SMD). Funnel plots and Egger's tests were utilized to evaluate for the presence of publication bias. RESULTS:A total of 19 studies met inclusion in the current systematic review. Meta-analysis revealed that MSCs have a significant positive effect on neurobehavioral outcome following HIE injury. Sensorimotor function was improved by 2.25 SMD (95% CI; 2.04-2.46) in cylinder rearing and 2.97 SMD (95% CI; 2.56-3.38) in rotarod. Likewise, cognitive function was improved by 2.76 SMD (95% CI; 2.53-2.98) on the water maze and 2.97 SMD (95% CI; 2.58-3.35) in object recognition. Stratification demonstrated an increased effect size depending on various study characteristics. CONCLUSIONS:Overall, these results suggest a promising role for MSCs in preclinical studies of HIE. MSC treatment demonstrates improved functional outcomes that are encouraging for future translational studies. While risk of bias and heterogeneity limited the strength of our meta-analysis, our results are consistent with those seen in this field of research.

Project description:BACKGROUND:Animal studies reporting immune checkpoint inhibitors (CPIs) improved host defense and survival during bacterial sepsis provided one basis for phase I CPI sepsis trials. We performed a systematic review and meta-analysis examining the benefit of CPI therapy in preclinical studies, and whether variables potentially altering this clinical benefit were investigated. Studies were analyzed that compared survival following bacteria or lipopolysaccharide challenge in animals treated with inhibitors to programmed death-1 (PD-1), PD-ligand1 (PD-L1), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), or B- and T-lymphocyte attenuator (BTLA) versus control. RESULTS:Nineteen experiments from 11 studies (n = 709) were included. All experiments were in mice, and 10 of the 19 were published from a single research group. Sample size calculations and randomization were not reported in any studies, and blinding procedures were reported in just 1. Across all 19 experiments, CPIs increased the odds ratio for survival (OR, 95% CI) [3.37(1. 55, 7.31)] but with heterogeneity (I2 = 59%, p < 0.01). After stratification by checkpoint molecule targeted, challenge site or type, or concurrent antibacterial treatment, CPIs had consistent effects over most experiments in the 9 that included antibacterial treatment [OR = 2.82 (1.60, 4.98), I2 = 6%, p = 0.39 with versus 4.01 (0.89, 18.05), I2 = 74%, p < 0.01 without]. All 9 antibiotic experiments employed cecal-ligation and puncture (CLP) bacterial challenge while 6 also included a Candida albicans challenge 3-4?days after CLP. In these six experiments (n = 322), CPIs were directed at the fungal challenge when CLP lethality had resolved, and were consistently beneficial [2.91 (2.41, 3.50), I2 = 0%, p = 0.99]. In the three experiments (n = 66) providing antibiotics without fungal challenge, CPIs were administered within 1 day of CLP and had variable and non-significant effects [0.05 (0.00, 1.03); 7.86 (0.28, 217.11); and 8.50 (0.90, 80.03)]. No experiment examined pneumonia. CONCLUSIONS:Preclinical studies showing that CPIs add benefit to antibiotic therapy for the common bacterial infections causing sepsis clinically are needed to support this therapeutic approach. Studies should be reproducible across multiple laboratories and include procedures to reduce the risk of bias.