MSC-Derived Extracellular Vesicles to Heal Diabetic Wounds: a Systematic Review and Meta-Analysis of Preclinical Animal Studies

Adrian J M Bailey; Heidi Li; Aidan M Kirkham; Alvin Tieu; Harinad B Maganti; Risa Shorr; Dean A Fergusson; Manoj M Lalu; Heidi Elomazzen; David S Allan

doi:10.1007/s12015-021-10164-4

MSC-Derived Extracellular Vesicles to Heal Diabetic Wounds: a Systematic Review and Meta-Analysis of Preclinical Animal Studies

Stem Cell Rev Rep. 2022 Mar;18(3):968-979. doi: 10.1007/s12015-021-10164-4. Epub 2021 Apr 24.

Authors

Adrian J M Bailey^{1

2

3}, Heidi Li¹, Aidan M Kirkham^{2

3}, Alvin Tieu^{1

3

4

5}, Harinad B Maganti^{2

3}, Risa Shorr⁶, Dean A Fergusson^{1

3

7

8}, Manoj M Lalu^{1

3

4

5

9}, Heidi Elomazzen², David S Allan^{10

11

12

13

14

15}

Affiliations

¹ Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
² Stem Cells and Centre for Innovation, Canadian Blood Services, Ottawa, Canada.
³ Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Canada.
⁴ Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Canada.
⁵ Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
⁶ Library and Information Services, The Ottawa Hospital, Ottawa, Canada.
⁷ Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Canada.
⁸ School of Public Health and Epidemiology, University of Ottawa, Ottawa, Canada.
⁹ Departments of Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, Canada.
¹⁰ Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. daallan@toh.ca.
¹¹ Stem Cells and Centre for Innovation, Canadian Blood Services, Ottawa, Canada. daallan@toh.ca.
¹² Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Canada. daallan@toh.ca.
¹³ Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Canada. daallan@toh.ca.
¹⁴ Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Canada. daallan@toh.ca.
¹⁵ Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Canada. daallan@toh.ca.

Abstract

Introduction: Extracellular 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.

Methods: PubMed 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.

Results: A 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.

Conclusion: MSC-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.

Registration: PROSPERO #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).

Keywords: Diabetes; Exosomes; Extracellular vesicles; Mesenchymal stromal cells; Wound healing.

Publication types

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

MeSH terms

Animals
Cicatrix
Diabetes Mellitus*
Extracellular Vesicles*
Mesenchymal Stem Cells*
Wound Healing