Integrating mechanical forces - a cellular mechanodampener

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To develop healthy body tissues, cells define their type and behaviour by following a genetic instruction manual. This is fine-tuned by responses to both biological and physical signals. Comparatively, our understanding of how tissue biology is shaped by changing physical forces is limited. This limits our appreciation of both tissue formation, maturation and of the processes that safeguard life-long tissue health. All tissues require the successful mixing of biological signals such as secreted proteins and physical signals. One example is flow in blood vessels, another is the formation of our skeleton whilst we move. Much of our skeleton is formed from cartilage, which transitions to bone in a highly coordinated process called endochondral ossification. The cartilage lining our joints must resist this pre-programmed transition but the cartilage that forms bone must control this change in cell identity and tissue environment. This shaping of our skeleton is both sensitive and resilient to physical forces. Recent evidence from studies in adolescent mice, strongly implicates a tiny compartment of cell called primary cilia in protecting programmed adjustments to cell type, regulated mineralisation of the environment and the formation of bone from cartilage. We hypothesise they use it to level out responses to unequal forces as our skeleton matures. We now wish to understand which cartilage cell subtypes use cilia to protect their behaviour in the context of force and what messaging they use to enable this. Secondly, we would like to use both mice and an engineered model of endochondral ossification to understand how cilia aid these processes and how we can use such models to understand the role of mechanics in shaping tissue development and health.