Ali, S; (2015) Dynamic Effect of Young’s Modulus on Attachment and Differentiation of Mouse Embryonic Stem Cells. Doctoral thesis , UCL (University College London).

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Abstract

Embryonic stem cells have generated much interest due to their ability to differentiate into any cell type within the body. This ability could potentially allow for scientists and engineers to develop a number of therapies for diseases, which currently have no cure such as Parkinson’s disease, Alzheimer’s disease and diabetes. However, the differentiation process itself is one of the major bottlenecks in developing potential therapies. Currently protocols involve the use of mixtures of growth factors in order to create a suitable soluble microenvironment for differentiation. These growth factors are often expensive, thereby limiting the potential for scale-up of cell bioprocesses. Much interest has thus been generated into other elements of the microenvironment that could improve differentiation efficiency. The field of mechanobiology in particular, has developed rapidly in recent years. The aim of this thesis was to investigate the effect of Young’s modulus on neuronal differentiation of mouse embryonic stem cells (mESC’s). Instead of treating differentiation as one long process, the decision was made to split the process into three stages. The first, involved the formation of neural precursors from mESC’s. This was followed by the formation of immature neurons from neural precursors. The final stage was to allow the immature neurons to develop into a mature neuronal subtype. The impact of Young’s modulus was split into three effects. One was the initial attachment of cells. The second was the expansion of cells into colonies. The third was the effect of Young’s modulus on enrichment of neuronal cells. It was found that physiologically soft materials favoured the formation of all three neuronal cell types (precursor, immature and mature). However, the exact effect of differentiation varied over the course of differentiation. Over the first and second stages, soft substrates favoured the initial attachment of cells without affecting enrichment. Over the final stage, however, soft substrates directly favoured maturation of immature neurons, without having a significant effect upon their attachment. Thus the effect of Young’s modulus on neuronal differentiation changes according to the level of cellular maturity. There have not been any previous studies, which have tried to characterise the effect of the mechanical microenvironment on differentiation in a stage-by-stage manner. These findings have many important implications in terms of regenerative medicine bioprocessing. Firstly the optimal conditions for cellular attachment are not always the same as the optimal conditions for increasing cell enrichment. By carefully fine-tuning the mechanical properties at each stage of differentiation, both cell yields and final enrichment could be increased substantially. Furthermore, different cell types will require different optimisation strategies. Finally, by better understanding the interaction between cells and their mechanical environment, these findings could allow for better future design of tissue engineering biomaterials for implantation of cells into target areas for cell therapies.

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