Stem Cells as Therapy for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis of Preclinical Studies

Eduardo Villamor-Martinez; Tamara Hundscheid; Boris W. Kramer; Carlijn R. Hooijmans; Eduardo Villamor-Martinez

doi:10.3389/fped.2020.578984

Stem Cells as Therapy for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis of Preclinical Studies

Eduardo Villamor-Martinez, Tamara Hundscheid, Boris W. Kramer, Carlijn R. Hooijmans, Eduardo Villamor-Martinez^*

^*Corresponding author for this work

Research output: Contribution to journal › (Systematic) Review article › peer-review

Abstract

Background: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal condition among very and extremely preterm infants. Stem cell therapy has shown some promising protective effects in animal models of intestinal injury, including NEC, but no systematic review has yet evaluated the preclinical evidence of stem cell therapy for NEC prevention or treatment.

Methods: PubMed and EMBASE databases were searched for studies using an animal model of NEC with stem cells or their products. The SYRCLE tool was used for the assessment of risk of bias. A random-effects model was used to pool odds ratios (ORs) and 95% confidence interval (CI).

Results: We screened 953 studies, of which nine (eight rat and one mouse models) met the inclusion criteria. All animal models induced NEC by a combination of hypothermia, hypoxia, and formula feeding. Risk of bias was evaluated as unclear on most items for all studies included. Meta-analysis found that both mesenchymal and neural stem cells and stem cell-derived exosomes reduced the incidence of all NEC (OR 0.22, 95% CI 0.16-0.32, k = 16), grade 2 NEC (OR 0.41, 95% CI 0.24-0.70, k = 16), and grade 3-4 NEC (OR 0.28, 95% CI 0.19-0.42, k = 16). k represents the number of independent effect sizes included in each meta-analysis. The effect of the exosomes was similar to that of the stem cells. Stem cells and exosomes also improved 4-day survival (OR 2.89 95% CI 2.07-4.04, k = 9) and 7-day survival (OR 3.96 95% CI 2.39-6.55, k = 5) after experimental NEC. Meta-analysis also found that stem cells reduced other indicators of intestinal injury.

Conclusion: The data from this meta-analysis suggest that both stem cells and stem cell-derived exosomes prevented NEC in rodent experimental models. However, unclear risk of bias and incomplete reporting underline that poor reporting standards are common and hamper the reliable interpretation of preclinical evidence for stem cell therapy for NEC.

Original language	English
Article number	578984
Number of pages	12
Journal	Frontiers in pediatrics
Volume	8
DOIs	https://doi.org/10.3389/fped.2020.578984
Publication status	Published - 9 Dec 2020

Keywords

stem cells
necrotizing enterocolitis (NEC)
preclinical (in-vivo) studies
meta-analysis
risk of bias assessment
ANIMAL-MODELS
BRONCHOPULMONARY DYSPLASIA
AMNIOTIC-FLUID
SEARCH FILTER
GROWTH-FACTOR
EXOSOMES
TRANSPLANTATION
IMPROVE

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10.3389/fped.2020.578984Licence: CC BY

Cite this

@article{8b7995e5de06474f8c84db00534b2372,

title = "Stem Cells as Therapy for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis of Preclinical Studies",

abstract = "Background: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal condition among very and extremely preterm infants. Stem cell therapy has shown some promising protective effects in animal models of intestinal injury, including NEC, but no systematic review has yet evaluated the preclinical evidence of stem cell therapy for NEC prevention or treatment.Methods: PubMed and EMBASE databases were searched for studies using an animal model of NEC with stem cells or their products. The SYRCLE tool was used for the assessment of risk of bias. A random-effects model was used to pool odds ratios (ORs) and 95% confidence interval (CI).Results: We screened 953 studies, of which nine (eight rat and one mouse models) met the inclusion criteria. All animal models induced NEC by a combination of hypothermia, hypoxia, and formula feeding. Risk of bias was evaluated as unclear on most items for all studies included. Meta-analysis found that both mesenchymal and neural stem cells and stem cell-derived exosomes reduced the incidence of all NEC (OR 0.22, 95% CI 0.16-0.32, k = 16), grade 2 NEC (OR 0.41, 95% CI 0.24-0.70, k = 16), and grade 3-4 NEC (OR 0.28, 95% CI 0.19-0.42, k = 16). k represents the number of independent effect sizes included in each meta-analysis. The effect of the exosomes was similar to that of the stem cells. Stem cells and exosomes also improved 4-day survival (OR 2.89 95% CI 2.07-4.04, k = 9) and 7-day survival (OR 3.96 95% CI 2.39-6.55, k = 5) after experimental NEC. Meta-analysis also found that stem cells reduced other indicators of intestinal injury.Conclusion: The data from this meta-analysis suggest that both stem cells and stem cell-derived exosomes prevented NEC in rodent experimental models. However, unclear risk of bias and incomplete reporting underline that poor reporting standards are common and hamper the reliable interpretation of preclinical evidence for stem cell therapy for NEC.",

keywords = "stem cells, necrotizing enterocolitis (NEC), preclinical (in-vivo) studies, meta-analysis, risk of bias assessment, ANIMAL-MODELS, BRONCHOPULMONARY DYSPLASIA, AMNIOTIC-FLUID, SEARCH FILTER, GROWTH-FACTOR, EXOSOMES, TRANSPLANTATION, IMPROVE",

author = "Eduardo Villamor-Martinez and Tamara Hundscheid and Kramer, {Boris W.} and Hooijmans, {Carlijn R.} and Eduardo Villamor-Martinez",

year = "2020",

month = dec,

day = "9",

doi = "10.3389/fped.2020.578984",

language = "English",

volume = "8",

journal = "Frontiers in pediatrics",

issn = "2296-2360",

publisher = "Frontiers Media S.A.",

}

TY - JOUR

T1 - Stem Cells as Therapy for Necrotizing Enterocolitis

T2 - A Systematic Review and Meta-Analysis of Preclinical Studies

AU - Villamor-Martinez, Eduardo

AU - Hundscheid, Tamara

AU - Kramer, Boris W.

AU - Hooijmans, Carlijn R.

AU - Villamor-Martinez, Eduardo

PY - 2020/12/9

Y1 - 2020/12/9

N2 - Background: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal condition among very and extremely preterm infants. Stem cell therapy has shown some promising protective effects in animal models of intestinal injury, including NEC, but no systematic review has yet evaluated the preclinical evidence of stem cell therapy for NEC prevention or treatment.Methods: PubMed and EMBASE databases were searched for studies using an animal model of NEC with stem cells or their products. The SYRCLE tool was used for the assessment of risk of bias. A random-effects model was used to pool odds ratios (ORs) and 95% confidence interval (CI).Results: We screened 953 studies, of which nine (eight rat and one mouse models) met the inclusion criteria. All animal models induced NEC by a combination of hypothermia, hypoxia, and formula feeding. Risk of bias was evaluated as unclear on most items for all studies included. Meta-analysis found that both mesenchymal and neural stem cells and stem cell-derived exosomes reduced the incidence of all NEC (OR 0.22, 95% CI 0.16-0.32, k = 16), grade 2 NEC (OR 0.41, 95% CI 0.24-0.70, k = 16), and grade 3-4 NEC (OR 0.28, 95% CI 0.19-0.42, k = 16). k represents the number of independent effect sizes included in each meta-analysis. The effect of the exosomes was similar to that of the stem cells. Stem cells and exosomes also improved 4-day survival (OR 2.89 95% CI 2.07-4.04, k = 9) and 7-day survival (OR 3.96 95% CI 2.39-6.55, k = 5) after experimental NEC. Meta-analysis also found that stem cells reduced other indicators of intestinal injury.Conclusion: The data from this meta-analysis suggest that both stem cells and stem cell-derived exosomes prevented NEC in rodent experimental models. However, unclear risk of bias and incomplete reporting underline that poor reporting standards are common and hamper the reliable interpretation of preclinical evidence for stem cell therapy for NEC.

AB - Background: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal condition among very and extremely preterm infants. Stem cell therapy has shown some promising protective effects in animal models of intestinal injury, including NEC, but no systematic review has yet evaluated the preclinical evidence of stem cell therapy for NEC prevention or treatment.Methods: PubMed and EMBASE databases were searched for studies using an animal model of NEC with stem cells or their products. The SYRCLE tool was used for the assessment of risk of bias. A random-effects model was used to pool odds ratios (ORs) and 95% confidence interval (CI).Results: We screened 953 studies, of which nine (eight rat and one mouse models) met the inclusion criteria. All animal models induced NEC by a combination of hypothermia, hypoxia, and formula feeding. Risk of bias was evaluated as unclear on most items for all studies included. Meta-analysis found that both mesenchymal and neural stem cells and stem cell-derived exosomes reduced the incidence of all NEC (OR 0.22, 95% CI 0.16-0.32, k = 16), grade 2 NEC (OR 0.41, 95% CI 0.24-0.70, k = 16), and grade 3-4 NEC (OR 0.28, 95% CI 0.19-0.42, k = 16). k represents the number of independent effect sizes included in each meta-analysis. The effect of the exosomes was similar to that of the stem cells. Stem cells and exosomes also improved 4-day survival (OR 2.89 95% CI 2.07-4.04, k = 9) and 7-day survival (OR 3.96 95% CI 2.39-6.55, k = 5) after experimental NEC. Meta-analysis also found that stem cells reduced other indicators of intestinal injury.Conclusion: The data from this meta-analysis suggest that both stem cells and stem cell-derived exosomes prevented NEC in rodent experimental models. However, unclear risk of bias and incomplete reporting underline that poor reporting standards are common and hamper the reliable interpretation of preclinical evidence for stem cell therapy for NEC.

KW - stem cells

KW - necrotizing enterocolitis (NEC)

KW - preclinical (in-vivo) studies

KW - meta-analysis

KW - risk of bias assessment

KW - ANIMAL-MODELS

KW - BRONCHOPULMONARY DYSPLASIA

KW - AMNIOTIC-FLUID

KW - SEARCH FILTER

KW - GROWTH-FACTOR

KW - EXOSOMES

KW - TRANSPLANTATION

KW - IMPROVE

U2 - 10.3389/fped.2020.578984

DO - 10.3389/fped.2020.578984

M3 - (Systematic) Review article

C2 - 33363060

SN - 2296-2360

VL - 8

JO - Frontiers in pediatrics

JF - Frontiers in pediatrics

M1 - 578984

ER -