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Fluid Dynamics Seminar

Monday, Mar. 21, 2011, 4:00 PM
Cullimor, Room 611
New Jersey Institute of Technology

Primary Cilia as Cellular Mechanosensors

Christopher R. Jacobs

Department of Biomedical Engineerin, Columbia University

Abstract

The ability of non-specialized non-excitable cells to sense and respond to mechanical stimulation is central to proper physiologic function in a surprisingly wide range of cell types including endothelial cells, liver, lung and kidney epithelial cells, chondrocytes, neurons, and osteocytes. Cellular mechanosensation is critical in diseases responsible for enormous human suffering including atherosclerosis, osteoarthritis, cancer, and osteoporosis. Primary cilia are solitary linear cellular extensions that extend from the surface of virtually all cells. As a result, large local strains occur as they are deflected suggesting that they may act as cellular strain concentrators. For decades, the biologic function of this enigmatic structure was elusive, however, recent data suggest that it functions as a complex nexus where both physical and chemical extracellular signals are sensed and coordinated responses initiated. For example, it is important in sensing the biochemical signals hedgehog (Hh), wingless, and platelet derived growth factor, as well as mechanosensing in the kidney and embryonic node. In our laboratory we have collected data that primary cilia act as mechanical sensors in bone cells. We have shown that osteocytes that have had their primary cilia deleted are unable to respond to dynamic fluid flow. We have also shown that mice that have had primary cilia conditionally deleted from bone cells are deficient in their ability to form bone in response to physical loading. Furthermore, we have found that the intracellular signaling pathway activated by primary cilia in bone is distinct from those observed in other tissues such as kidney. We have implicated the second messenger cAMP and the enzyme responsible for its regulation, adenylyl cyclase 6, in the primary-cilium-dependent pathway activated by dynamic flow in osteocytes. Finally, we have developed a novel beam-bending model to describe the deformation of primary cilia in terms of flexural rigidity and basal rotation. In conclusion, the primary cilium has a rich potential to transduce a variety of signals through multiple mechanisms and may undergo functional specialization as a function of tissue or cell type.