Guzmán Herrera, Alejandra; (2023) Mechanics of Organoid Formation and Repair. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mechanics has an important effect on tissue morphology during development and regeneration, influencing how efficiently a tissue repairs itself. The liver is an organ with striking regenerative abilities that has been widely studied at a molecular and genetic level, however, the mechanical aspect remains unclear. While the study of such processes has recently been facilitated by the development of liver organoids that recapitulate a ductal regenerative response in vitro, the main focus has remained on the underlying molecular and genetic details. Nonetheless, the importance of tissue morphology and mechanics has become more apparent. The aim of this project is to better understand the role mechanics play in liver regenerative morphogenesis using mouse organoids. I first characterise organoid morphology, which starts as a spherical and translucent cell monolayer that either remains spherical or becomes more complex and multi-layered upon differentiation. I then provide evidence that the final morphology of differentiated liver organoids correlates with their cell composition. Interestingly, complex morphologies also emerge without chemical differentiation. Since the mechanoenvironment has been shown to induce and regulate cell differentiation, I investigate the effect of substrate mechanical properties (i.e. stiffness) on liver organoids. The data suggests substrate stiffness does have an important effect on organoid morphologies and their cell profile. Finally, I examine the mechanical properties of the organoids themselves, how they change as they differentiate, and how this affects their ability to respond to further damage. The results show the fluid state of progenitor organoids changes after differentiation, impacting how the cells respond to injury. By studying the mechanical aspect of liver regenerative morphogenesis in organoids, we hope to contribute to a better understanding of how and why the injured tissue chooses one mechanism over another amongst the numerous ways in which the liver can respond to injury.

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