Background and aims Preterm infants are prone to hypoxic-ischaemic encephalopathy. No therapy exists to treat this brain injury. The objective of this study was to assess the neuroprotective effect of exogenous administration of stem cells and the mobilisation of endogenous stem cells in the ovine preterm brain after global hypoxia-ischemia.
Methods Instrumented preterm sheep were subjected to global hypoxia-ischemia by 25 min of umbilical cord occlusion at a gestational age of 104 (term is 150) days. During a 7 day reperfusion period all vital parameters, including (amplitude-integrated) electroencephalogram, were recorded. At the end of the experiment, the preterm brain was assessed by histology and diffusion tensor imaging (DTI).
Results Systemic administration of exogenous mesenchymal stem cells (MSCs) reduced cerebral inflammation (i.e. microglia proliferation) and white matter injury. MSCs induced T-cell tolerance, which was paralleled with diminished mobilisation and invasion of these cells in the preterm brain. In addition, MSCs decreased number of seizures after global hypoxia-ischemia, indicating functional improvement.
Similarly, mobilisation of endogenous stem cells using systemic granulocyte-colony stimulating factor (G-CSF) reduced cerebral inflammation and white matter injury. However, G-CSF did not reduce the number of seizures after global hypoxia-ischemia.
Conclusion We have shown for the first time in a translational animal model that cell-based therapy is effective in protecting the preterm brain against the cerebral and peripheral inflammatory responses which are involved in the aetiology of white matter injury in the preterm brain after global hypoxia-ischemia. Our studies form the basis for future clinical trials studying feasibility of cell-based therapy in preterm infants with hypoxic-ischaemic encephalopathy.
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