Villamor-Martinez Eduardo, Hundscheid Tamara, Kramer Boris W, Hooijmans Carlijn R, Villamor Eduardo
Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, Netherlands.
Department for Health Evidence Unit SYRCLE, Radboud University Medical Center, Nijmegen, Netherlands.
Front Pediatr. 2020 Dec 9;8:578984. doi: 10.3389/fped.2020.578984. eCollection 2020.
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. 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). 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, = 16), grade 2 NEC (OR 0.41, 95% CI 0.24-0.70, = 16), and grade 3-4 NEC (OR 0.28, 95% CI 0.19-0.42, = 16). 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, = 9) and 7-day survival (OR 3.96 95% CI 2.39-6.55, = 5) after experimental NEC. Meta-analysis also found that stem cells reduced other indicators of intestinal injury. 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.
坏死性小肠结肠炎（NEC）是极早产儿和超早产儿中最常见的危及生命的胃肠道疾病。干细胞疗法在包括NEC在内的肠道损伤动物模型中显示出一些有前景的保护作用，但尚无系统评价评估干细胞疗法预防或治疗NEC的临床前证据。检索了PubMed和EMBASE数据库，以查找使用NEC动物模型和干细胞或其产物的研究。使用SYRCLE工具评估偏倚风险。采用随机效应模型汇总比值比（OR）和95%置信区间（CI）。我们筛选了953项研究，其中9项（8项大鼠模型和1项小鼠模型）符合纳入标准。所有动物模型均通过低温、缺氧和配方奶喂养联合诱导NEC。纳入的所有研究在大多数项目上的偏倚风险评估为不清楚。荟萃分析发现，间充质干细胞、神经干细胞和干细胞衍生的外泌体均降低了所有NEC的发生率（OR 0.22，95%CI 0.16-0.32，I² = 16）、2级NEC的发生率（OR 0.41，95%CI 0.24-0.70，I² = 16）以及3-4级NEC的发生率（OR 0.28，95%CI 0.19-0.42，I² = 16）。I²代表每项荟萃分析中纳入的独立效应量的数量。外泌体的作用与干细胞相似。干细胞和外泌体还改善了实验性NEC后的4天生存率（OR 2.89，95%CI 2.07-4.04，I² = 9）和7天生存率（OR 3.96，95%CI 2.39-6.55，I² = 5）。荟萃分析还发现干细胞降低了肠道损伤的其他指标。该荟萃分析的数据表明，干细胞和干细胞衍生的外泌体均可在啮齿动物实验模型中预防NEC。然而，偏倚风险不清楚和报告不完整表明，报告标准不佳很常见，这妨碍了对干细胞疗法治疗NEC的临床前证据进行可靠解读。
