Investigating the therapeutic efficacy of cellular therapy for neonatal ischemic injury
AuthorKagan, Brett J.
AffiliationFlorey Department of Neuroscience and Mental Health
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2020-11-20.
© 2018 Dr Brett J. Kagan
Improvements in medical science have drastically increased survival for infants suffering from neonatal arterial ischemic stroke (NAIS). However, the failure to reverse the associated injuries has resulted in increased numbers of patients suffering from chronic neurodevelopmental disability. Potentially, stem cell-based therapy offers the greatest potential as a viable therapeutic tool not only for neuro-protection but importantly also for neural repair and restabilising lost connections. However, there is still vital investigations to be performed in the optimisation of cellular therapy as a medically effective tool, along with gaining a more comprehensive understanding of the mechanisms of actions and difference utility between different cell types. This research firstly aimed to develop a technically simple, high-throughput rodent model of NAIS affecting the cortex to be able to effectively test cellular therapy. Refined behavioural and cognitive testing procedures were also required to test the functional recovery offered by this therapy and this work aimed to develop and assess the validity of these methods. Ultimately, this work aimed to test the therapeutic efficacy human pluripotent cells differentiated to a cortical progenitor cells as a method of directly replacing damaged tissue. Moreover, this therapy was directly compared to the use of human umbilical cord blood cells (hUCBCs) as a therapy, with the aim of determining the relative value each of these therapies as potential treatments following NAIS. A technically simple, high-throughput rodent model of NAIS was developed. Utilising this model, two separate studies were conducted testing the therapeutic efficacy of pluripotent cells differentiated to cortical progenitor cells vs multipotent UBCs as a treatment of neonatal ischemic stroke. Holistically, the data indicated that grafts of cortical progenitors but not hUCBCs improved behavioural outcomes compared to ischemia alone. Moreover, a comparable level of atrophy among stroke induced groups was found at the target site. However, a reduction in atrophy relative to lesion alone groups distal to the target site was observed in the groups which received cortically differentiated pluripotent cells. Moreover, cortical progenitor cells were found to significantly protect white matter while hUCBC administration was found to show exacerbated white matter damage relative to controls. Cortically differentiated cells offer meaningful protection of neural tissue, particularly white matter, and assist in functional recovery following NAIS. In contrast, UBCs transplanted to the site of injury consistently exacerbated damage caused by NAIS. When this cell type was instead administered intravenously, as done currently in human clinical trials for NAIS, no consistent difference was found for low doses, other than a subtle deficit on the reversal task for pairwise discrimination, while a high dose was associated with a significant degree of damage to white matter. Treatments using human UBCs is typically described as safe, justifying their use in human clinical trials despite little evidence of substantial and consistent gain of function for NAIS in pre-clinical research. These findings challenge this long held assumption of safety, replicating this finding over two studies. In contrast, compelling evidence was found to the support the use of neural progenitor cells as a therapeutic option following neonatal ischemic stroke. Overall, studies in both humans and animals investigating therapy for NAIS should explicitly assess for potential damage caused by cellular therapy, rather than assuming safety. Moreover, the cell type adopted for therapy should be rigorously justified by robust pre-clinical research before moving to clinical trials.
Keywordscerebral palsy; ischemic stroke; neonatal stroke; stem cell; cell therapy; human umbilical blood cord cells; embryonic stem cells; induced pluripotent stem cells; animal models
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