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.

Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

“…Over the past decade, stem cells have been studied as a potential avenue of treatment, however the therapeutic benefit of MSCs in the intestinal pathogenesis of NEC has yet to be fully explored in the clinical setting ( 77 , 82 , 95 , 96 ). In fact, only one clinical case report shows a benefit of stem cells used in a case of surgical NEC where umbilical-cord-derived-MSCs (UC-MSCs) were given intravenously.…”

Efficacy of mesenchymal stromal cells in preclinical models of necrotizing enterocolitis: a systematic review protocol

“…In 2020, a systematic review and meta-analysis of preclinical studies using animal models of NEC with stem cells products was published. 40 This study suggests a benefit of stem cells in rodent models. However, the research in stem cells is a rapid-growing field in medicine and we believe that an update review with broad inclusion criteria is needed.…”

Necrotizing enterocolitis in premature infants—A defect in the brakes? Evidence from clinical and animal studies

“…Several microRNAs, including miR-146, let-7, and miR-21, are also known to inhibit TLR signaling by translational repression of targeted mRNAs and intraperitoneal injections with miR-21 decreased severity of enteral LPS-induced experimental NEC in newborn rats 22 , 128 – 131 . Finally, stem cells or exosomes derived from stem cells exert their beneficial effect in NEC partly by inhibiting TLR and other inflammatory pathways, although the precise mechanisms remain unclear 132 – 134 . Together, these studies that mediate TLR inhibition in the gut provide additional evidence to support the loss of the brakes on TLR in NEC pathogenesis.…”