Introduction: Hypoxic ischemic (HI) insults during pregnancy and birth can result in long term neurodevelopmental disorders, such as cerebral palsy. We have previously shown that a single dose of human umbilical cord blood (hUCB) cells was able to improve long-term behavioural outcomes, but was not able to modulate neuropathological outcomes. In this current study we aimed to compare the effect of a single dose versus multiple doses of hUCB cells on long-term neuropathological and behavioural outcomes. We hypothesised that multiple doses of hUCB would be more effective than a single dose.
Methods: HI injury was induced in postnatal day (PND) 10 rats by left carotid artery ligation, followed by 90min of hypoxia (8% oxygen). 24h later, pups were administered hUCB cells and received 1 dose (PND11), or 3 doses (PND11, 13, 20). Rats were monitored until PND50; throughout this period, they underwent extensive behavioural testing. On PND50, brains were collected for immunohistological analysis.
Results: Following HI, there was a decrease in brain weight (P=0.025) and left hemisphere tissue area (P=0.0006) compared to sham and multiple doses of hUCB cells significantly improved brain weight (P=0.015) and reduced tissue loss (P=0.046). There was an increase in apoptosis in both the somatosensory cortex and motor cortex in the HI group compared to sham (P= 0.0006 and 0.0059 respectively). Apoptosis was significantly reduced with repeated administration of hUCB cells in both regions (P=0.0098 and 0.0125 respectively) compared to HI. In addition, there was a significant reduction in overall behavioural score following HI compared to sham (P=0.003), this deficit was significantly ameliorated following treatment with multiple doses of hUCB (P=0.0054), but not a single dose.
Conclusion: Treatment with repeated doses of hUCB cells is more effective than a single dose for reducing long-term tissue damage and restoring behavioural deficits following perinatal brain injury.