In WP1, we have tested the optimal dose, route and timing of H-MSC delivery for neuroprotection in two small animal models of EoP based on postnatal inflammation and in utero periventricular haemorrhage. We have demonstrated the superiority of the intranasal (versus intravenous) delivery route at a late stage with robust regeneration being afforded in both models.
In WP2, we are using two large animal models of EoP (chorioamnionitis and birth-asphyxia models) to study the short- term and long-term effects of H-MSC. The ovine studies have been successfully performed for the short and long-term chorioamnionitis model cohorts and the short-term birth asphyxia model cohort. Analysis of histopathological alterations, MRI data as well as motor and cognitive functions is ongoing in order to examine the neuroprotective effect of H-MSC.
In WP3, we are assessing the potential beneficial effects of H-MSC on multiple target cells important during EoP using in vitro co-culture systems. We have shown beneficial effects of H-MSC on all target cells including immunomodulatory effects on peripheral immune cells and microglia, rescue effects on challenged neurons, maturation and survival effects on challenged oligodendrocytes, and boosting and differentiating effects on neural stem cells. We also studied if two preconditioning protocols (hypoxic exposure (HP-H-MSC) or creatine preloading (CP-H-MSC)) could yield superior H-MSC effects compared to naïve H-MSC actions. We observed superior effects of HP-H-MSC on neurons and neural stem cells, and superior effects of CP-H-MSC on oligodendrocytes, neural stem cells and microglia. We will finalize all in vitro experiments to generate data needed for the final regeneration matrix of WP3.
In WP4, we are using five rodent models involving the four major current paradigms of EoP: inflammation, fluctuation of oxygen concentrations combined with inflammation, placental dysfunction and periventricular haemorrhage. We found clear-cut model-related differences in neuronal and glial injury and differences in neural cell maturation which are counterbalanced by H-MSC treatment. All models assessing microglia and astrocyte responses showed an increased local inflammatory response, ameliorated by H-MSC.
In WP5, functional ultrasound (fUS) and ultrasound localization microscopy (ULM) have been implemented in 3D for whole-brain imaging in rodents, and applied for preliminary investigations of vascular alterations in mouse models of neuroinflammation.
WP6 strives for visibility and impact of PREMSTEM and builds on previously applied methods to create interest for the project’s overall cause. The co-creation process was completed and a report which will be available to the public has been compiled. The Patient/Consumer Advisory Board has contributed to the project and given valuable insight. The exploitation and sustainability strategy has been updated, reviewed and presented internally.
In WP7, we organized two annual General Assembly meetings and five Executive Committee meetings. We prepared and submitted on behalf of the consortium two progress and financial reports to the EC.
In WP8, the PREMSTEM consortium ensures the continuous addressing of ethical questions.
