Umbilical Cord Blood-Derived Cell Therapy for Perinatal Brain Injury: A Systematic Review & Meta-Analysis of Preclinical Studies

Abstract

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. To systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury. 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. 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. 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.

Keywords: brain injury; cerebral palsy; fetal blood; hypoxic ischemic encephalopathy; infant; intraventricular haemorrhage; newborn.

Figure 1

PRISMA diagram detailing study selection process.

Figure 2

Forest plot demonstrating the effect of umbilical cord blood-derived cell therapy on (A) Infarct size; (B) Neuron number; (C) Oligodendrocyte number—grey matter; (D) Oligodendrocyte number—white matter; (E) Apoptosis—grey matter; (F) Apoptosis—white matter. Umbilical cord blood-derived cell therapy significantly decreased infarct size (p < 0.00001), increased neuron number (p < 0.001), increased oligodendrocyte number in both grey matter (p < 0.0005) and white matter (p = 0.02), and decreased apoptosis in both grey matter (p = 0.0005) and white matter (p < 0.0001). Abbreviations: admin, administration; ECFC, endothelial colony forming cells; EPC, endothelial progenitor cell; HSCs, haemopoietic stem cells; ICV, intracerebroventricular; IV, intravenous; MNC, mononuclear cell; PCB, preterm cord blood; TCB, term cord blood; Treg, T-regulatory cells; UCBC, umbilical cord blood cells.

Figure 2

Forest plot demonstrating the effect of umbilical cord blood-derived cell therapy on (A) Infarct size; (B) Neuron number; (C) Oligodendrocyte number—grey matter; (D) Oligodendrocyte number—white matter; (E) Apoptosis—grey matter; (F) Apoptosis—white matter. Umbilical cord blood-derived cell therapy significantly decreased infarct size (p < 0.00001), increased neuron number (p < 0.001), increased oligodendrocyte number in both grey matter (p < 0.0005) and white matter (p = 0.02), and decreased apoptosis in both grey matter (p = 0.0005) and white matter (p < 0.0001). Abbreviations: admin, administration; ECFC, endothelial colony forming cells; EPC, endothelial progenitor cell; HSCs, haemopoietic stem cells; ICV, intracerebroventricular; IV, intravenous; MNC, mononuclear cell; PCB, preterm cord blood; TCB, term cord blood; Treg, T-regulatory cells; UCBC, umbilical cord blood cells.

Figure 3

Forest plot demonstrating the effect of umbilical cord blood-derived cell therapy on (A) Astrogliosis—grey matter; (B) Astrogliosis—white matter; (C) Microglia activation—grey matter; (D) Microglia activation- white matter. Umbilical cord blood-derived cell therapy significantly decreased astrogliosis in both grey matter (p = 0.01) and white matter (p = 0.006), and decreased microglia activation in both grey matter (p < 0.0001) and white matter (p = 0.001).Abbreviations: admin, administration; ECFC, endothelial colony forming cells; EPC, endothelial progenitor cell; ICV, intracerebroventricular; IV, intravenous; MNC, mononuclear cell; PCB, preterm cord blood; TCB, term cord blood; Treg, T-regulatory cells; UCBC, umbilical cord blood cells.

Figure 3

Forest plot demonstrating the effect of umbilical cord blood-derived cell therapy on (A) Astrogliosis—grey matter; (B) Astrogliosis—white matter; (C) Microglia activation—grey matter; (D) Microglia activation- white matter. Umbilical cord blood-derived cell therapy significantly decreased astrogliosis in both grey matter (p = 0.01) and white matter (p = 0.006), and decreased microglia activation in both grey matter (p < 0.0001) and white matter (p = 0.001).Abbreviations: admin, administration; ECFC, endothelial colony forming cells; EPC, endothelial progenitor cell; ICV, intracerebroventricular; IV, intravenous; MNC, mononuclear cell; PCB, preterm cord blood; TCB, term cord blood; Treg, T-regulatory cells; UCBC, umbilical cord blood cells.

Figure 4

Forest plot demonstrating the effect of umbilical cord blood-derived cell therapy on neuroinflammation (A) TNF-α; (B) IL-6; (C) IL-1β; (D) IL-10. Umbilical cord blood-derived cell therapy significantly decreased neuroinflammation as measured by TNF-α (p < 0.0001), IL-6 (p < 0.01) and IL-1β (p = 0.001). Abbreviations: admin, administration; ICV, intracerebroventricular; IV, intravenous; PCB, preterm cord blood; TCB, term cord blood; UCBC, umbilical cord blood cells.

Figure 4

Forest plot demonstrating the effect of umbilical cord blood-derived cell therapy on neuroinflammation (A) TNF-α; (B) IL-6; (C) IL-1β; (D) IL-10. Umbilical cord blood-derived cell therapy significantly decreased neuroinflammation as measured by TNF-α (p < 0.0001), IL-6 (p < 0.01) and IL-1β (p = 0.001). Abbreviations: admin, administration; ICV, intracerebroventricular; IV, intravenous; PCB, preterm cord blood; TCB, term cord blood; UCBC, umbilical cord blood cells.

Figure 5

Forest plot demonstrating the effect of umbilical cord blood-derived cell therapy on motor function (A) Cylinder test; (B) Rotarod test. Umbilical cord blood-derived cell therapy significantly improved motor function as measured by cylinder test (p = 0.0003) and rotarod test (p = 0.002) Abbreviations: admin, administration; UCBC, umbilical cord blood cells.

Figure 6

Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment.