Speech:

Integrative cellular mechanobiology and biomechanics and the emergence of primary cilia as mechanosensors

Abstract
Cellular mechanosensation is critical in diseases responsible for enormous human suffering including atherosclerosis, osteoarthritis, cancer, and osteoporosis. Nonetheless, very little is understood about the molecular mechanisms of mechanotransduction outside of a small number of specialized sensory cells. Primary cilia are solitary linear cellular extensions that extend from the surface of virtually all cells. For decades, the biologic function of these enigmatic structures was elusive, however, recent evidence suggests an emerging picture in which the primary cilium functions as a complex nexus where both physical and chemical extracellular signals are sensed and responses coordinated.

A 3D reconstruction of cells (red) with their primary (green).

In our laboratory we have shown that primary cilia act as mechanical sensors in bone and that conditional deletion of primary cilia lead to mechanosensing defects. Additionally mice that receive bone marrow transplants from donors lacking primary cilia have a blunted response to loading, suggesting that they are important in stem cell proliferation, differentiation, migration, and/or engraftment. Recently, we developed a novel combined experimental/modeling approach to determine the mechanical properties of primary cilia. We found a wide variety of previously unreported deformation modes including smooth bending and rigid-body rotations. This suggests that the mechanics of both the cilium shaft and basal anchorage are important to understanding deflection patterns. Interestingly, both the cilium itself and its anchorage to the microtubule cytoskeleton alter their structure in response to physical loading, suggesting structural adaptation or “remodeling”. We have also developed novel molecular biology tools to elucidate the details of mechanically activated ciliary signaling pathways. For example, we have created a cilia-directed biosensor that has allowed us to distinguish intraciliary from intracellular calcium signaling. We have also developed a method for distinguishing the roles of the cytoplasmic and ciliary pools of proteins that are found in both compartments. In summary, primary cilia are non-linear, richly varied, mechanical structures (biomechanics) as well as structurally adaptive (mechanobiology). Simultaneously they are a biochemical microdomain where signaling events are catalyzed, enhanced, and integrated. It seems likely that we have only just begun to appreciate the wide range of cellular functions and dysfunction in which primary cilia play a crucial role.