MSC-Derived Extracellular Vesicles in Preclinical Animal Models of Bone Injury: A Systematic Review and Meta-Analysis

Aidan M Kirkham; Adrian J M Bailey; Alvin Tieu; Harinad B Maganti; Joshua Montroy; Risa Shorr; T Mark Campbell; Dean A Fergusson; Manoj M Lalu; Heidi Elmoazzen; David S Allan

doi:10.1007/s12015-021-10208-9

MSC-Derived Extracellular Vesicles in Preclinical Animal Models of Bone Injury: A Systematic Review and Meta-Analysis

Stem Cell Rev Rep. 2022 Mar;18(3):1054-1066. doi: 10.1007/s12015-021-10208-9. Epub 2021 Jul 27.

Authors

Aidan M Kirkham^{1

2}, Adrian J M Bailey^{1

2}, Alvin Tieu^{2

3

4

5}, Harinad B Maganti^{1

2}, Joshua Montroy², Risa Shorr⁶, T Mark Campbell^{3

4

7}, Dean A Fergusson^{2

4

5}, Manoj M Lalu^{2

3

8

9}, Heidi Elmoazzen¹, David S Allan^{10

11

12

13

14}

Affiliations

¹ Stem Cells, Canadian Blood Services, Ottawa, ON, Canada.
² Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada.
³ Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
⁴ Medicine, The Ottawa Hospital, Ottawa, ON, Canada.
⁵ Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁶ Medical Information and Education Services, The Ottawa Hospital, Ottawa, ON, Canada.
⁷ Department of Physical Medicine and Rehabilitation, Elisabeth Bruyère Hospital, Ottawa, ON, Canada.
⁸ Departments of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, ON, Canada.
⁹ School of Public Health and Epidemiology, University of Ottawa, Ottawa, ON, Canada.
¹⁰ Stem Cells, Canadian Blood Services, Ottawa, ON, Canada. daallan@toh.ca.
¹¹ Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada. daallan@toh.ca.
¹² Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada. daallan@toh.ca.
¹³ Medicine, The Ottawa Hospital, Ottawa, ON, Canada. daallan@toh.ca.
¹⁴ Biochemistry, Microbiology & Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. daallan@toh.ca.

PMID: 34313927
DOI: 10.1007/s12015-021-10208-9

Abstract

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

Keywords: Bone; Exosomes; Extracellular vesicles; Fracture; Mesenchymal stromal cells; Microvesicles; Regeneration; Repair.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Animals
Extracellular Vesicles* / metabolism
Mesenchymal Stem Cells* / metabolism
Models, Animal