Umbilical cord blood-derived cell therapy for perinatal brain injury: A systematic review & meta-analysis of preclinical studies - Part A

ABSTRACT Introduction Perinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived cell therapy as potential treatment. Objectives To systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury. Methods MEDLINE and Embase databases were searched for relevant studies. Brain injury outcomes were extracted for meta-analysis to calculate standard mean difference (SMD) with 95% confidence interval (CI), using an inverse variance, random effects model. Outcomes were separated based on grey matter (GM) and white matter (WM) regions where applicable. Risk of bias was assessed using SYRCLE, and GRADE was used to summarise certainty of evidence. Results Fifty-five eligible studies were included (7 large, 48 small animal models). UCB-derived cell therapy significantly improved outcomes across multiple domains, including decreased infarct size (SMD 0.53; 95%CI (0.32, 0.74), P<0.00001), apoptosis (WM, SMD 1.59; 95%CI (0.86, 2.32), P<0.0001), astrogliosis (GM, SMD 0.56; 95%CI (0.12, 1.01), P=0.01), microglial activation (WM, SMD 1.03; 95%CI (0.40, 1.66), P=0.001), neuroinflammation (TNF- α , SMD 0.84; 95%CI (0.44, 1.25), P<0.0001); as well as improved neuron number (SMD 0.86; 95%CI (0.39, 1.33), P=0.0003), oligodendrocyte number (GM, SMD 3.35; 95%CI (1.00, 5.69), P=0.005) and motor function (cylinder test, SMD 0.49; 95%CI (0.23, 0.76), P=0.0003). Risk of bias was determined as serious, and overall certainty of evidence was low. Conclusions UCB-derived cell therapy is an efficacious treatment in pre-clinical models of perinatal brain injury, however findings are limited by low certainty of evidence. SIGNIFICANCE STATEMENT Perinatal brain injury can lead to significant long-term neurodevelopmental deficits. There are limited treatment options available, and new interventions are urgently required. Through assessment of preclinical studies, this systematic review and meta-analysis shows that umbilical cord blood-derived cell therapy is an efficacious treatment for perinatal brain injury across a wide range of neuropathological and functional domains, albeit with low certainty of evidence. It also identified knowledge gaps, including that future studies should focus on non-hypoxic ischemic models, preterm models, large animal models and should explore the heterogeneity that exists in treatment protocols.