Abstract
The adult human central nervous system (CNS) has very limited regenerative capability, and injury at the cellular and molecular level cannot be studied in vivo. Modelling neural damage in human systems is crucial to identifying species-specific responses to injury and potentially neurotoxic compounds leading to development of more effective neuroprotective agents. Hence we developed human neural stem cell (hNSC) 3-dimensional (3D) cultures and tested their potential for modelling neural insults, including hypoxic-ischaemic and Ca2+-dependent injury. Standard 3D conditions for rodent cells support neuroblastoma lines used as human CNS models, but not hNSCs, but in all cases changes in culture architecture alter gene expression. Importantly, response to damage differs in 2D and 3D cultures and this is not due to reduced drug accessibility. Together, this study highlights the impact of culture cytoarchitecture on hNSC phenotype and damage response, indicating that 3D models may be better predictors of in vivo response to damage and compound toxicity.
Highlights
In light of the practical and ethical limitations of human research, animal models provide fundamental insight into the central nervous system (CNS) development, injury, disease, as well as the possibility of studying and screening putative therapeutic compounds
In 3D cultures, most neuroblastoma cells initially were round shaped with thin neurites extending into the matrix, but by two days in culture they displayed a tendency to aggregate rather than spreading out (Supplementary Fig. 1A)
Proliferative activity and viability of the neuroblastoma cells embedded in collagen hydrogels was confirmed by BrdU and propidium iodide (PI) staining respectively (Fig. 1D,E)
Summary
In light of the practical and ethical limitations of human research, animal models provide fundamental insight into the central nervous system (CNS) development, injury, disease, as well as the possibility of studying and screening putative therapeutic compounds. Further studies on the cell ular mechanisms of human CNS injury and repair are needed in order to develop better therapeutic strategies and bridge the gap between animal models and human clinical trials[7,8]. We first assessed the behaviour of different human neural cells, neuroblastoma, hNSCs and hNSC-derived neurons, in different hydrogels and polystyrene scaffolds in 3D as compared to 2D monolayer cultures. This led to selecting a 3D system consisting of Matrigel and Collagen I for modelling neural damage induced by calcium imbalance and hypoxic-ischemic injury. HNSC-derived neurons were found to be more resistant to calcium dependent injury than hNSCs
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