1. Epidemiology and Global Health
  2. Human Biology and Medicine
Download icon

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. University of Ottawa, Canada
  4. The University of Edinburgh, United Kingdom
  5. University of Calgary, Canada
  6. St. Michaels Hospital, The University of Toronto, Canada
  7. University of British Columbia, Canada
Research Article
Cite this article as: eLife 2016;5:e17850 doi: 10.7554/eLife.17850
4 figures and 4 tables

Figures

Preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram for study selection.
https://doi.org/10.7554/eLife.17850.003
Figure 2 with 11 supplements
Forest plot summarizing effects of mesenchymal stromal cell (MSC) therapy on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect of MSC therapy on mortality is depicted by the diamond at the bottom of the plot (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al. (2014) was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.005
Figure 2—figure supplement 1
Forest plot summarizing relationship of compatibility of donor mesenchymal stromal cell (MSC) with recipient animal (xenogenic vs syngeneic vs allogeneic vs autologous) on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.006
Figure 2—figure supplement 2
Forest plot summarizing relationship of mesenchymal stromal cell (MSC) dose on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.007
Figure 2—figure supplement 3
Forest plot summarizing relationship of mesenchymal stromal cell (MSC) therapy timing of administration on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.008
Figure 2—figure supplement 4
Forest plot summarizing relationship of mesenchymal stromal cell (MSC) administration route (intravenous vs intraperitoneal) on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.009
Figure 2—figure supplement 5
Forest plot summarizing relationship of mesenchymal stromal cell (MSC) tissue source (adipose vs bone marrow vs umbilical cord tissue) on mortality in preclinical models of sepsis and endotoxemia.

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.010
Figure 2—figure supplement 6
Forest plot summarizing relationship of animal species (rat vs mouse) on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.011
Figure 2—figure supplement 7
Forest plot summarizing relationship of animal sex (male vs female vs unreported) on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.012
Figure 2—figure supplement 8
Forest plot summarizing relationship of preclinical models of sepsis and endotoxemia (cecal ligation and puncture vs live bacteria administration vs bacterial product such as lipopolysaccharide) on mortality following treatment with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.013
Figure 2—figure supplement 9
Forest plot summarizing relationship of resuscitation (fluids +/- antibiotics vs no resuscitation) on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.014
Figure 2—figure supplement 10
Forest plot summarizing relationship of comparison (control) treatment on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.015
Figure 2—figure supplement 11
Forest plot summarizing relationship of adherence to elements of construct validity on mortality in preclinical models of sepsis and endotoxemia treated with mesenchymal stromal cells (MSCs).

Subgroups are studies that adhered to a majority of elements suggested to increase construct validity (≥5 of 8; see text for details of elements) vs those that did not adhere to majority. Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect is depicted by the diamond at the bottom of each subgroup (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al 2014 was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.016
Forest plot summarizing relationship of mesenchymal stromal cell (MSC) therapy on mortality over time in preclinical models of sepsis and endotoxemia (outcome windows: ≤2 days, >2 to ≤ 4 days, > 4 days).

Point estimates (odds ratio) and 95% confidence intervals (CI) are depicted for individual studies; size of point estimate depicts relative contribution to pooled effect. A pooled meta-analytic summary (random effects model) of overall effect of MSC therapy on mortality is depicted by the diamond at the bottom of each time interval (vertical points represent odds ratio point estimate and horizontal points represent 95% CIs). Heterogeneity is represented with the I2 statistic. Data from Pedrazza et al. (2014) was included in total counts but not included in meta-analysis due to 100% mortality in both study arms.

https://doi.org/10.7554/eLife.17850.017
Funnel plot to detect publication bias.

Trim and fill analysis was performed on overall mortality. Open circles denote original data, black circles denote ‘filled’ studies. Open diamond denotes original pooled effect size (log odds ratio) and 95% confidence interval. Filled diamond represents adjusted effect size and 95% confidence interval.

https://doi.org/10.7554/eLife.17850.021

Tables

Table 1

General characteristics of preclinical studies investigating the efficacy of mesenchymal stromal cells in models of sepsis.

https://doi.org/10.7554/eLife.17850.004
Author year
Country
Species,
Strain,
Gender
Sepsis modelResuscitationMSC source,
Compatibility
MSC
Dose
Time (hours)*MSC routeControl
Gonzalez-Rey et al. (2009)A
Spain
Mouse
BALB/c, NR
CLP
(1 × 22 G)
NoneAdipose
Xenogenic or Allogeneic
1.0 × 1064IPDMEM
Gonzalez-Rey et al. (2009)B
Spain
Mouse
BALB/c, NR
LPS
(i.p.)
NoneAdipose
Xenogenic
1.0 x 106 or3.0 x 1050.5IPDMEM
Nemeth et al. (2009)
United States
Mouse C57BL/6, MCLP
(2 × 21 G)
Fluid and antibioticsBone marrow
Allogeneic
1.0 × 1060 or 1IVPBS or
Fibroblast
Bi et al. (2010)
China
Mouse
C57BL/6, NR
CLP
(2 × 21 G)
NoneBone marrow
Xenogenic
1.0 × 1061 1IVPBS
Mei et al. (2010)A
Canada
Mouse C57BL/6J, FCLP
(1 × 22 G)
FluidBone marrow
Syngeneic
2.5 × 1056IVNS
Mei et al. (2010)B
Canada
Mouse C57BL/6J, FCLP
(1 × 18 G)
Fluid and
antibiotics
Bone marrow
Syngeneic
2.5 × 1056IVNS
Liang et al. (2011)
China
Rat
Wistar, F
LPS
(i.v.)
NoneBone marrow
Syngeneic
1.0 × 1062IVNS
Chang et al. (2012)
China
Rat
SPD, M
CLP
(2 × 18 G)
NoneAdipose
Autologous
3 × 1.2 × 1060.5, 6 then 18IPNS
Krasnodembskaya et al. (2012), USAMouse C57BL/6J, MP. aeruginosa
(i.p.)
NoneBone marrow
Xenogenic
1.0 × 1061IVPBS
Fibroblast
Li et al. (2012)
China
Rat
SPD, M
LPS
(i.p.)
NoneUmbilical cord
Xenogenic
5.0 × 1051IVNS or
Fibroblast
Hall et al. (2013)
USA
Mouse
BALB/c, M
CLP
(2 × 21 G)
NoneBone marrow
Syngeneic
1 × 5.0× 105
+ 2× 2.5 × 105
2 then
24 then 48
IVPBS or
Fibroblast
Zhao et al. (2013)
China
Rat
SPD, F
LPS
(i.v.)
NoneBone marrow
Syngeneic
2.5 ×1062IVNS
Chao et al. (2014)
Taiwan
Rat
Wistar, M
CLP
(1 × 18 G)
NoneBone Marrow or
Umbilical Cord Xenogenic
5.0 × 1064IVPBS
Kim et al. (2014)
Canada
Mouse C57BL/6, MSEB+
(i.p)
NoneBone marrow
Syngeneic
2.5 × 1053IVPBS
Luo et al. (2014)
China
Mouse C57Bl/6, MCLP
(2 × 21 G)
FluidBone marrow
Syngeneic
1.0 × 1063IVNS
Pedrazza et al. (2014)
Brazil
Mouse C57BL/6, ME. coli
(i.p.)
NoneAdipose
Syngeneic
1.0 × 1060IVPBS
Sepulveda et al. (2014)
Spain
Mouse
BALB/c, M
LPS
(i.p.)
NoneBone Marrow
Xenogenic
1.0 × 1060.5IPPBS
Zhao et al. (2014)
China
Mouse C57BL/6, MCLP
(NR)
NoneUmbilical cord
Xenogenic
1.0 × 1061IVNS
Zhou et al. (2014)
China
Mouse
NOD SCID, M
LPS+
(i.p.)
NoneUmbilical Cord
Xenogenic
2.0 × 1066IVNo treatment
Yang et al. (2015)
China
Mouse
NOD SCID, M
LPS+
(i.p.)
NoneUmbilical cord
Xenogenic
5.0 × 1050IVDMEM
  1. Legend: * = Time of delivery post-sepsis induction, + = Models also administered D-galactosamine, CLP = Cecal ligation and puncture, DMEM = Dulbecco's modified Eagle's medium, i.p. = Intraperitoneal, i.v. = Intravenous, LPS = Lipopolysaccharide, NR = Not reported, NOD SCID = NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (immunodeficient), NS = Normal saline, PBS = Phosphate buffered saline, SEB = Staphylococcal enterotoxin B, SPD = Sprague-Dawley.

Table 2

Risk of bias assessment of preclinical studies investigating the efficacy of mesenchymal stromal cells in models of sepsis.

https://doi.org/10.7554/eLife.17850.018
StudyRandomizationAllocation concealmentBlinding of personnelBlinding of outcome assessmentIncomplete outcome dataSelective outcome reporting
Gonzalez-Rey et al. (2009)UUUULL
Nemeth et al. (2009)UUUULL
Bi et al. (2010)UUUUHL
Mei et al. (2010)UUUULL
Liang et al. (2011)UUUUUL
Chang et al. (2012)UUUUUL
Krasnodembskaya et al. (2012)UUUUUL
Li et al. (2012)UUUUUL
Hall et al. (2013)UUUUUL
Zhao et al. (2013)UUUUUL
Chao et al. (2014)UUUUUL
Kim et al. (2014)UUUHUL
Luo et al. (2014)UUUUUL
Pedrazza et al. (2014)UUUUUL
Sepulveda 2014UUUUUL
Zhao et al. (2014)UUUUUL
Zhou et al. (2014)UUUUHL
Yang et al. (2015)UUUUUL
  1. Legend: H = High risk of bias, L = Low risk of bias, U = Unclear risk of bias

  2. Blinding of Outcome Assessment for Mortality: Low risk = Outcome assessors were blinded to the study groups when assessing mortality through surrogate endpoints or animals were allowed to die. Unclear = Insufficient information to determine if outcome assessors were blinded during assessment or if animals were allowed to die. High Risk = Outcome assessors not blinded to the study groups and death was defined according to surrogate endpoints.

  3. Incomplete Outcome Data: Low risk = N values were consistent between methods and results for the mortality outcome. Unclear = N value was either not presented in the methods or in the results, and therefore there is insufficient information to permit judgement. High risk = N values were not consistent between methods and results for the mortality outcome.

  4. Selective Reporting: Low risk = The methods section indicated mortality as a pre-specified outcome measure. High risk = The mortality outcome was presented in the results but not pre-specified in the methods section.

Table 3

Risk of bias assessment (other domains) of preclinical studies investigating the efficacy of mesenchymal stromal cells in models of sepsis.

https://doi.org/10.7554/eLife.17850.019
  1. Legend: * = Items modified from SYRCLE risk of bias tool, H = High risk of bias, L = Low risk of bias, U = Unclear risk of bias

  2. Baseline Characteristics: Low risk = Baseline severity of disease equal between experimental groups, Unclear = Baseline severity of disease unreported, High risk = Baseline severity of disease unbalanced between experimental groups.

  3. Random Housing: Low risk = Animal cages were randomly placed within an animal room/facility, Unclear = Housing placement unreported, High risk = Animals place in non-random arrangement in animal room/facility.

  4. Other risk of bias was assessed according to source of funding, conflict of interest and pre-specified sample size calculations:

  5. Source of Funding: Low risk = Non-industry source of funding (or no funding). Unclear = Funding source was not reported. High risk = Study was funded by industry.

  6. Conflict of Interest: Low risk = Authors reported on no conflict of interest. Unclear = Conflict of interest was not reported. High risk = Authors reported on potential conflict of interests.

  7. Sample Size Calculation: Low risk = Sample size calculations were correctly performed and followed. Unclear = Sample size calculations were not performed. High risk = Sample size calculations were incorrectly performed/followed.

Table 4

Construct validity assessment of preclinical studies investigating the efficacy of mesenchymal stromal cells in models of sepsis.

https://doi.org/10.7554/eLife.17850.020

Study

Large animal modelAdult animal modelComorbiditiesInfectious model of sepsisTherapy initiated after sepsis inductionDocumented sepsis severity prior to initiating treatmentResuscitation included antibioticsResuscitation included fluids

Gonzalez-Rey et al. (2009)A

NNNYYNNN

Gonzalez-Rey et al. (2009)B

NNNNYNNN

Nemeth et al. (2009)

NYNYYNYY

Bi et al. (2010)

NUNYYNNN

Mei (2010)A

NYNYYNNY

Mei (2010)B

NYNYYNYY

Liang et al. (2011)

NUNNYNNN

Chang et al. (2012)

NUNYYNNN

Krasnodembskaya et al. (2012)

NYNYYNNN

Li et al. (2012)

NUNNYNNN

Hall et al. (2013)

NUNYYNNN

Zhao et al. (2013)

NYNNYNNN

Chao et al. (2014)

NUNYYNNN

Kim et al. (2014)

NYNNYNNN

Luo et al. (2014)

NUNYYNNY

Pedrazza et al. (2014)

NYNYNNNN

Sepulveda 2014

NYNNYNNN

Zhao et al. (2014)

NUNYYNNN

Zhou et al. (2014)

NNYNYNNN

Yang et al. (2015)

NNYNNNNN
  1. Legend: N = No, U = Unclear, Y = Yes. Letters following author and year (e.g. Mei 2010A) indicate that more than one independent experiment was conducted in the same publication.

  2. Large Animal Model: Yes = Sheep, pig, dog, monkey. No = Mouse, rat

  3. Adult Animal Model: Yes = Rats ≥ 6 weeks old, mice ≥ 8 weeks old. No = Rats < 6 weeks old, mice < 8 weeks old. Unclear = No age stated

  4. Comorbidities: Yes = e.g. Diabetes, obesity, immunodeficiency. No = No comorbidities.

  5. Infectious Model of Sepsis: Yes = Cecal-ligation and puncture, live bacterial administration. No = Bacterial product administration (e.g. lipopolysaccharide).

  6. Therapy Initiated After Sepsis Induction: Yes = Mesenchymal stromal cells administered after sepsis model induced. No = Mesenchymal stromal cells administered at the time of sepsis induction.

  7. Documented Sepsis Severity Prior to Initiating Treatment: Yes = Mesenchymal stromal cells administered after marker of severity (e.g. hypotension) measured. No = Mesenchymal stromal cells administered without a marker of severity being measured.

  8. Resuscitation Included Fluids: Yes = Fluid therapy (aside from vehicle for cell administration) administered. No = Only vehicle for cell administration or no fluids administered.

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)

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

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