Human Umbilical Cord-Derived Cells Therapy for Hypoxic-Ischemic Encephalopathy: A Systematic Review and Meta-Analysis of Animal Models.

Introduction: Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe neurological disorder associated with high mortality and long-lasting complications in survivors. Umbilical cord-derived cells have emerged as promising therapeutic candidates, demonstrating positive results in experimental HIE research. This review systematically evaluates the current preclinical evidence on the efficacy of umbilical cord-derived cells in animal models of HIE, focusing on their effects on neurological function and identifying research gaps and constraints that need to be addressed for future preclinical and clinical studies. Methods: The present systematic review and meta-analysis, conducted in accordance with the Systematic Review Protocol for Animal Intervention Studies, synthesized the available evidence on the efficacy of umbilical cord-derived cells. Relevant studies were searched for in Medline's PubMed, Web of Science, Embase, and Cochrane databases up to May 1, 2024. Papers that included the interventional use of UC-derived cells were considered, regardless of the source, dose, timing, and frequency. Nevertheless, studies involving modified UC-derived cells or combination therapies were excluded. Functional neurological outcomes were extracted for meta-analysis to calculate standardized mean difference (SMD) with 95% confidence interval (CI), using a random effects model. The risk of bias was evaluated using SYRCLE. Forest plots and funnel plots were utilized to evaluate potential publication bias. Results: Twelve studies were incorporated into the systematic review. The meta-analysis indicated a significant positive impact of umbilical cord-derived cells on neurobehavioral outcomes post-HIE injury. Sensorimotor function showed an improvement of 0.80 SMD (95% CI, 0.58-1.03) in the negative geotaxis test, while cognitive function demonstrated a 1.44 SMD (95% CI, 1.21-1.67) improvement in the water maze test. The subgroup analysis demonstrated heterogeneous effect sizes contingent on distinct study characteristics, including animal age, cell type, cell dosage, delivery method, and timing method. Conclusions: Overall, these findings suggest a promising role for umbilical cord-derived cells in preclinical HIE studies. The treatment with umbilical cord-derived cells exhibited enhanced functional outcomes, showing promise for future translational research. Despite limitations such as bias risk and heterogeneity affecting the meta-analysis robustness, our results align with existing literature in this research domain. Trial Registration: ClinicalTrials.gov identifier: CRD42024551469.