MSC-Derived Extracellular Vesicles in Preclinical Animal Models of Bone Injury: A Systematic Review and Meta-Analysis,Stem Cell Reviews and Reports

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MSC-Derived Extracellular Vesicles in Preclinical Animal Models of Bone Injury: A Systematic Review and Meta-Analysis
Stem Cell Reviews and Reports ( IF 4.5 ) Pub Date : 2021-07-27 , DOI: 10.1007/s12015-021-10208-9
Aidan M Kirkham _{1,

2} , Adrian J M Bailey _{1,

2} , Alvin Tieu _{2,

3,

4,

5} , Harinad B Maganti _{1,

2} , Joshua Montroy ₂ , Risa Shorr ₆ , T Mark Campbell _{3,

4,

7} , Dean A Fergusson _{2,

4,

5} , Manoj M Lalu _{2,

3,

8,

9} , Heidi Elmoazzen ₁ , David S Allan _{1,

2,

3,

4,

10}

Affiliation

Background and Objective

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are a promising treatment for bone injuries, although studies remain preclinical. A systematic review and meta-analysis can assess the efficacy of MSC-EVs and identify treatment aspects associated with enhanced bone repair.

Methods

English language, preclinical, controlled, in vivo studies identified in our systematic search (up to May 8, 2020) examining the use of MSC-EVs in bone healing were included. Risk of bias (ROB) was assessed using the SYRCLE tool. Aggregate Data Meta-Analysis was performed to determine the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) and New Bone Formation (NBF).

Results

Thirteen studies were included. Twelve reported either BV/TV or NBF and were included in meta-analysis. ROB was unclear in all studies. Overall, MSC-EVs displayed benefit in terms of bone healing for both BV/TV (22.2% mean difference (MD); 95% CI: 15.8–28.5%, p < 0.001) and NBF (26.1% MD; 10.3–41.8%, p = 0.001) versus controls. Substantial heterogeneity, however, was observed between studies. MSC-EVs were reported to activate multiple signaling pathways including mTOR/AKT, AMPK and BMP2. Subgroup analysis indicated no significant difference in the improvement of BV/TV when using modified EVs isolated after gene transfection, preconditioning (p = 0.61), or using EVs in combination with a tissue scaffold and/or hydrogel versus other delivery methods (p = 0.20).

Conclusion

Use of MSC-EVs to promote healing of bone injury appears promising, however, heterogeneity between studies and the potential for reporting bias limits confidence in the extent of benefit. Reducing bias between studies and addressing aspects of potential reporting bias should augment confidence in future meta-analyses and propel the field towards clinical studies.

Graphical Abstract

Forest Plot analysis assessing the percentage change in bone volume (BV) / total volume (TV) in the presence (experimental) or absence (control) of MSC-EVs.

中文翻译：

骨损伤临床前动物模型中 MSC 衍生的细胞外囊泡：系统评价和荟萃分析

背景与目的

间充质基质细胞衍生的细胞外囊泡 (MSC-EVs) 是一种很有前途的骨损伤治疗方法，尽管研究仍处于临床前阶段。系统回顾和荟萃分析可以评估 MSC-EV 的功效并确定与增强骨修复相关的治疗方面。

方法

在我们的系统搜索（截至 2020 年 5 月 8 日）中确定的英语语言、临床前、对照、体内研究检查了 MSC-EV 在骨愈合中的使用。使用 SYRCLE 工具评估偏倚风险 (ROB)。进行汇总数据元分析以确定 MSC-EV 对骨体积/总体积 (BV/TV) 和新骨形成 (NBF) 的影响。

结果

包括十三项研究。12 人报告了 BV/TV 或 NBF，并被纳入荟萃分析。ROB 在所有研究中都不清楚。总体而言，MSC-EVs 在 BV/TV（22.2% 平均差（MD）；95% CI：15.8-28.5%，p < 0.001）和 NBF（26.1% MD；10.3-41.8%）的骨愈合方面显示出益处, p = 0.001) 与对照。然而，在研究之间观察到了显着的异质性。据报道，MSC-EV 可激活多种信号通路，包括 mTOR/AKT、AMPK 和 BMP2。亚组分析表明，在基因转染、预处理（ p = 0.61）或使用 EV 与组织支架和/或水凝胶结合使用后分离的改良 EV 与其他递送方法相比，BV/TV 的改善没有显着差异。p = 0.20）。