The mechanical environment of the stem cell niche in bone marrow
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Understanding how bone marrow mesenchymal stem cells (MSCs) contribute to new bone formation and remodelling in vivo is of principal importance for informing the development of effective bone tissue engineering strategies in vitro. However, the precise stimuli for osteogenic differentiation of MSCs in vivo have not been fully established. The work presented in this thesis uses a combination of experimental and computational modelling approaches to investigate the in vivo environment of the stem cell niche in bone marrow, with a specific goal of identifying important biochemical and mechanical cues for osteogenic differentiation of MSCs. Support cells within the niche are examined for their roles in osteogenic differentiation. Specifically osteocytes and osteoblasts are examined due to their established role as regulatory cells in bone. Osteocytes are found to be more dominant than osteoblasts. However, when cultured together, a synergistic relationship is found to exist between them, for stimulating the osteogenic differentiation of MSCs. Fluid structure interaction (FSI) models are used to determine whether MSCs can be directly stimulated by mechanical cues within the bone marrow. Models predict that the shear stress generated due to physiological loading is within the stimulatory range (maximum values range from 0.025 - 0.25 Pa). Additionally, it is found that the onset of osteoporosis can alter the shear stress within the marrow. Explanted samples of trabecular bone and marrow are physiologically compressed and are found to have greater osteogenic activity, as verified by bone histomorphometry, compared to static samples. FSI models demonstrate that bone strain, not marrow shear stress, is likely the driving mechanical signal during compression. To focus on shear stress in the marrow, low-magnitude high-frequency vibration loading is used as this induces minimal bone strain while generating marrow shear stress. µ-CT analysis shows strong bone formation and remodelling in vibration samples compared to static samples. Computational models reveal a significant relationship between this formation and remodelling and shear stress in the marrow. Together the results of this PhD thesis demonstrate that: (1) osteocytes and osteoblasts can stimulate osteogenic differentiation of MSCs. (2) Shear stress of sufficient magnitude to stimulate the osteogenic differentiation of MSCs, is generated during compression, but this can be altered in osteoporotic bone. (3) In vivo responses of bone to compression loading are replicated in explanted samples; however, models indicate that bone strain is the dominant signal. Finally, (4) explanted samples exposed to vibrational loading experience more marrow shear stress than in compression loading, and the magnitude of the shear stress has a causal role in the formation of bone and improvement in bone architecture parameters.