Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial

  1. Manoj M Lalu
  2. Katrina J Sullivan
  3. Shirley HJ Mei
  4. David Moher
  5. Alexander Straus
  6. Dean A Fergusson
  7. Duncan J Stewart
  8. Mazen Jazi
  9. Malcolm MacLeod
  10. Brent Winston
  11. John Marshall
  12. Brian Hutton
  13. Keith R Walley
  14. Lauralyn McIntyre  Is a corresponding author
  15. on behalf of the Canadian Critical Care Translational Biology Group
  1. The Ottawa Hospital, Canada
  2. The Ottawa Hospital Research Institute, Canada
  3. The University of Edinburgh, United Kingdom
  4. University of Calgary, Canada
  5. St. Michaels Hospital, The University of Toronto, Canada
  6. University of Ottawa, Canada

Abstract

Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality (odds ratio 0.27, 95% confidence interval 0.18-0.40, latest timepoint reported for each study) over a range of experimental conditions. Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a ~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies.

Article and author information

Author details

  1. Manoj M Lalu

    Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0322-382X
  2. Katrina J Sullivan

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Shirley HJ Mei

    Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. David Moher

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Alexander Straus

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Dean A Fergusson

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Duncan J Stewart

    Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9113-8691
  8. Mazen Jazi

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Malcolm MacLeod

    Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Brent Winston

    Department of Critical Care Medicine, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. John Marshall

    Departments of Surgery and Critical Care Medicine, Keenan Research Centre of the Li KaShing Knowledge Institute, St. Michaels Hospital, The University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Brian Hutton

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Keith R Walley

    Department of Medicine, University of Ottawa, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Lauralyn McIntyre

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    For correspondence
    lmcintyre@ohri.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7421-1407

Funding

National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/L000970/1)

  • David Moher

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2016, Lalu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,244
    views
  • 450
    downloads
  • 68
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Manoj M Lalu
  2. Katrina J Sullivan
  3. Shirley HJ Mei
  4. David Moher
  5. Alexander Straus
  6. Dean A Fergusson
  7. Duncan J Stewart
  8. Mazen Jazi
  9. Malcolm MacLeod
  10. Brent Winston
  11. John Marshall
  12. Brian Hutton
  13. Keith R Walley
  14. Lauralyn McIntyre
  15. on behalf of the Canadian Critical Care Translational Biology Group
(2016)
Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial
eLife 5:e17850.
https://doi.org/10.7554/eLife.17850

Share this article

https://doi.org/10.7554/eLife.17850

Further reading

    1. Epidemiology and Global Health
    2. Genetics and Genomics
    Tianyu Zhao, Hui Li ... Li Chen
    Research Article

    Alzheimer’s disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD.

    1. Epidemiology and Global Health
    Xiaoning Wang, Jinxiang Zhao ... Dong Liu
    Research Article

    Artificially sweetened beverages containing noncaloric monosaccharides were suggested as healthier alternatives to sugar-sweetened beverages. Nevertheless, the potential detrimental effects of these noncaloric monosaccharides on blood vessel function remain inadequately understood. We have established a zebrafish model that exhibits significant excessive angiogenesis induced by high glucose, resembling the hyperangiogenic characteristics observed in proliferative diabetic retinopathy (PDR). Utilizing this model, we observed that glucose and noncaloric monosaccharides could induce excessive formation of blood vessels, especially intersegmental vessels (ISVs). The excessively branched vessels were observed to be formed by ectopic activation of quiescent endothelial cells (ECs) into tip cells. Single-cell transcriptomic sequencing analysis of the ECs in the embryos exposed to high glucose revealed an augmented ratio of capillary ECs, proliferating ECs, and a series of upregulated proangiogenic genes. Further analysis and experiments validated that reduced foxo1a mediated the excessive angiogenesis induced by monosaccharides via upregulating the expression of marcksl1a. This study has provided new evidence showing the negative effects of noncaloric monosaccharides on the vascular system and the underlying mechanisms.