Abstract
Developmental brain injury after extreme preterm birth, also known as ‘Encephalopathy of Prematurity (EoP)’, is commonly encountered in the neonatal intensive care unit and can lead to life-long neurodevelopmental impairments. At this time, treatment options to improve brain development after extreme preterm birth are still lacking. This thesis aimed to
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elucidate the cellular and molecular mechanisms underlying cerebral dysmaturation in EoP and to explore the potential of novel treatment options to improve brain development after extreme preterm birth.
A double-hit mouse model of EoP was developed to investigate the underlying mechanisms of brain injury. In this model, the combination of postnatal hypoxia-ischemia and systemic inflammation caused transient global dysmaturation of the immature brain, closely mimicking the clinical situation. Experimental induction of EoP was associated with myelination deficits, impaired oligodendrocyte maturation, aberrant interneuron development, neuroinflammation, behavioral impairments and global volumetric deficits of white and gray matter structures.
We used our validated mouse model to investigate whether intranasally administered mesenchymal stem cell (MSCs) can promote brain development after EoP. Early intranasal treatment with MSCs restored oligodendrocyte maturation and myelination, improved interneuron development and dampened astrocyte and microglia activation. Anatomical recovery was accompanied by improvement of functional outcome. MSCs were shown to exert their regenerative properties through adaptation of their secretome in situ, contributing to a cerebral environment permissive for endogenous repair through the release of trophic and anti-inflammatory factors. Delay of cell administration significantly reduced the therapeutic efficacy of MSCs. Modification of MSCs, with transient hypersecretion of selected growth factors, was shown to prolong the treatment window for effective MSC treatment after EoP.
In a similar manner, the therapeutic potential of intranasal insulin-like growth factor 1 (IGF1) treatment was studied using our double-hit mouse model of EoP. Early intranasal administration of IGF1 was shown to boost oligodendrocyte maturation and restore interneuron abnormalities, thereby improving functional outcome. In contrast to MSC treatment, intranasal administration of IGF1 dampened astrocyte activation, but not microglia activity after EoP induction. We showed that this observation is likely the result of differential expression of the IGF1 receptor on cells of the brain.
In our clinical study we explored the relationship between postnatal blood levels of IGF1 and its binding protein IGFBP3 and neurodevelopmental outcome after extreme preterm birth. In our cohort of extreme preterm infants, higher blood levels of IGFBP3, but not IGF1, were associated with a reduction in brain injury severity, increased regional brain volumes and improved white matter structural integrity at term. Future studies are needed to further investigate the potential role of IGFBP3 as an early biomarker for EoP.
In conclusion, we propose that both early intranasal MSC and IGF1 treatment show great promise to support brain development after EoP. Additional studies, aimed at refining the optimal treatment protocol, are needed for future translation of these promising therapeutic strategies to clinical care.
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