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A Systematic Review of Preclinical Studies on the Therapeutic Potential of Mesenchymal Stromal Cell-Derived Microvesicles

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Abstract

Background

The therapeutic potential of mesenchymal stromal cells (MSCs) may be largely mediated by paracrine factors contained in microvesicles (MV) released from intracellular endosomes. A systematic review of controlled interventional animal studies was performed to identify models of organ injury where clinical translation of MSC-derived microvesicle therapy appears most promising as regenerative therapy.

Methods

A total of 190 published articles were identified in our systematic search of electronic databases (MEDLINE, EMBASE, PUBMED). After screening for eligibility, a total of 17 controlled studies testing MSC-derived MVs as therapeutic interventions in animal models of disease underwent comprehensive review, quality assessment, and data extraction.

Results

Thirteen studies addressed the regenerative potential following organ injury. Six studies were included on acute kidney injury, 4 on myocardial infarction and reperfusion injury, 1 on hind limb ischemia, 1 on liver injury, and 1 on hypoxic lung injury. Four studies addressed immunological effects of MSC-derived MVs on inhibiting tumor growth. Twelve studies (71 %) provided explicit information regarding the number of animals allocated to treatment or control groups. Five studies (29 %) randomly assigned animals to treatment or control groups and only 1 study (6 %) reported on blinding. Therapeutic intervention involved isolation of exosomes (40–100 nm) in eight studies, while nine studies tested unfractionated microvesicles (<1,000 nm). In studies of tissue regeneration, all 13 reported that treatment with MSC-derived MVs improved at least one major/clinical parameter associated with organ dysfunction. Three of 4 studies evaluating the inhibition of tumor growth reported benefit.

Conclusions

In preclinical studies, the use of MSC-derived MVs is strongly associated with improved organ function following injury and may be useful for inhibiting tumor growth. Improved preclinical study quality in terms of treatment allocation reporting, randomization and blinding will accelerate needed progress towards clinical trials that should assess feasibility and safety of this therapeutic approach in humans.

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Acknowledgments

We wish to acknowledge the expertise and assistance of Risa Shorr from the library at The Ottawa Hospital for help with design and execution of the systematic search. Funding support for CA was provided by The Ottawa Hospital Foundation Research Fund for Hematology and Blood and Marrow Transplantation. Salary support from a New Investigator Award (DSA) and Mentorship Award in Clinical Trials (JT) was generously provided by Canadian Institutes of Health Research. An endowed Chair in Clinical Epidemiology (DF) from the University of Ottawa (U of O) and Ottawa Hospital Research Institute is gratefully acknowledged. DSA and JT are supported in part by the Department of Medicine at U of O. Part of this work was undertaken as part of the Science and Technology program of the Canadian Government, AECL Project 1.4.4-8 Improving Occupational Dosimetry.

Disclosures

The authors indicate no potential conflicts of interest.

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Authors and Affiliations

  1. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada

    Celine Akyurekli, Yevgeniya Le & David S. Allan

  2. Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada

    Dean Fergusson & Jason Tay

  3. Department of Medicine, Hematology, University of Ottawa, Ottawa, ON, Canada

    Jason Tay & David S. Allan

  4. Atomic Energy of Canada Limited, Chalk River, Ottawa, ON, Canada

    Yevgeniya Le & Richard B. Richardson

  5. Ottawa Hospital Research Institute, Box 704, 501 Smyth Rd, Ottawa, ON, Canada, K1H 8 L6

    David S. Allan

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  1. Celine Akyurekli
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Correspondence to David S. Allan.

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Akyurekli, C., Le, Y., Richardson, R.B. et al. A Systematic Review of Preclinical Studies on the Therapeutic Potential of Mesenchymal Stromal Cell-Derived Microvesicles. Stem Cell Rev and Rep 11, 150–160 (2015). https://doi.org/10.1007/s12015-014-9545-9

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