Abstract
Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 106 MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE.
Highlights
Preterm infants are prone to brain injury after a perinatal hypoxic-ischemic insult [1,2,3].Hypoxic-ischemic encephalopathy (HIE) in preterm infants is predominantly characterized by white matter injury which is caused by damage to highly vulnerable immature oligodendrocytes [1,2,4]
No differences were found in MABP, FHR, pH, arterial partial oxygen pressure or arterial partial carbon dioxide pressure between the HI-SAL and HI-mesenchymal stem cells (MSC) group, indicating that the physiological response to umbilical cord occlusion (UCO) and the degree of acidosis, hypoxemia and hypercarboxemia was similar in all animals exposed to global HI (Figure 2)
Our findings demonstrated that intravenous administration of MSC reduced the cerebral inflammatory response in the hypoxic-ischemic preterm brain after global HI
Summary
Preterm infants are prone to brain injury after a perinatal hypoxic-ischemic insult [1,2,3].Hypoxic-ischemic encephalopathy (HIE) in preterm infants is predominantly characterized by white matter injury (i.e. periventricular leukomalacia) which is caused by damage to highly vulnerable immature oligodendrocytes [1,2,4]. We showed in this model, which is representative for brain development of preterm infants, that global HI induced a profound microglial response followed by a second peripheral inflammatory response characterized by invasion of mobilized peripheral immune cells into the ischemic preterm ovine brain [11]. These inflammatory changes were associated with marked injury to pre-oligodendrocytes and hypomyelination of the preterm brain [11], which are well known indicators of white matter injury in the ischemic preterm brain [1,2,12]. Our findings indicated that the immature immune system is readily mobilized after global HI and is involved in the etiology of white matter injury, the clinical hallmark of hypoxic-ischemic preterm brain injury [11]
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