A Systematic Review of Preclinical Studies on the Therapeutic Potential of Mesenchymal Stromal Cell-Derived Microvesicles
- 3.9k Downloads
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.
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.
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.
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.
KeywordsMesenchymal stromal cells Microvesicles Exosomes Preclinical Animal models Systematic review
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.
The authors indicate no potential conflicts of interest.
- 9.Ionescu, L., Byrne, R. N., van Haaften, T., et al. (2012). Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. American Journal of Physiology Lung Cellular and Molecular Physiology, 303, L967–L977.CrossRefPubMedCentralPubMedGoogle Scholar
- 19.Henderson, V. C., Kimmelman, J., Fergusson, D., Grimshaw, J. M., & Hackam, D. G. (2013). Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS Medicine, 10, e1001489.CrossRefPubMedCentralPubMedGoogle Scholar
- 22.Gatti, S., Bruno, S., Deregibus, M. C., Sordi, A., Cantaluppi, V., Tetta, C., et al. (2011). Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrology Dialysis Transplantation, 26, 1474–1483.CrossRefGoogle Scholar
- 24.Reis, L. A., Borges, F. T., Simoes, M. J., Borges, A. A., Sinigaglia-Coimbra, R., & Schor, N. (2012). Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats. PloS One, 7, e44092.CrossRefPubMedCentralPubMedGoogle Scholar
- 25.Zhou, Y., Xu, H., Xu, W., Wang, B., Wu, H., Tao, Y., et al. (2013). Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Research Therapy, 4, 34.CrossRefPubMedCentralPubMedGoogle Scholar
- 26.Arslan, F., Lai, R. C., Smeets, M. B., Akeroyd, L., Choo, A., Aguor, E. N. E., et al. (2013). Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Research, 10, 301–312.CrossRefPubMedGoogle Scholar
- 28.Lai, R. C., Arslan, F., Tan, S. S., Tan, B., Choo, A., Lee, M. M., et al. (2010). Derivation and characterization of human fetal MSCs: an alternative cell source for large-scale production of cardioprotective microparticles. Journal of Molecular and Cellular Cardiology, 48, 1215–1224.CrossRefPubMedGoogle Scholar
- 30.Zhang, H. C., Liu, X. B., Huang, S., Bi, X. Y., Wang, H. X., Xie, L. X., et al. (2012). Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells and Development, 21, 3289–3297.CrossRefPubMedCentralPubMedGoogle Scholar
- 36.Rosu-Myles M, Gillham-Eisen LA, Agbanyo FR, Ganz PR (2011) Regulatory questions in the development of blood stem cell products for regenerative therapy. In: Regenerative Therapy Using Blood-Derived Stem Cells ed. DS Allan and D Strunk, Springer Science, pp 167–190Google Scholar