Mechanical Properties of a Primary Cilium As Measured by Resonant Oscillation

Resnick, Andrew

doi:10.1016/j.bpj.2015.05.031

Cited by 22 publications

(26 citation statements)

References 58 publications

(39 reference statements)

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“…Following [39, 48], we model the cilium as a 1-D nonlinear uniform cantilevered beam. This basic model for a primary cilium treats a cilium as a homogeneous flexible cylindrical beam, anchored at the basal end and free to move at the distal end.…”

Section: Methodsmentioning

confidence: 99%

HIF Stabilization Weakens Primary Cilia

Resnick

2016

PLoS ONE

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Although solitary or sensory cilia are present in most cells of the body and their existence has been known since the sixties, very little is known about their functions. One suspected function is fluid flow sensing- physical bending of cilia produces an influx of Ca++, which can then result in a variety of activated signaling pathways. Defective cilia and ciliary-associated proteins have been shown to result in cystic diseases. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a progressive disease, typically appearing in the 5th decade of life and is one of the most common monogenetic inherited human diseases, affecting approximately 600,000 people in the United States. Because the mechanical properties of cilia impact their response to applied flow, we asked how the stiffness of cilia can be controlled pharmacologically. We performed an experiment subjecting cilia to Taxol (a microtubule stabilizer) and CoCl2 (a HIF stabilizer to model hypoxia). Madin-Darby Canine Kidney (MDCK) cells were selected as our model system. After incubation with a selected pharmacological agent, cilia were optically trapped and the bending modulus measured. We found that HIF stabilization significantly weakens cilia. These results illustrate a method to alter the mechanical properties of primary cilia and potentially alter the flow sensing properties of cilia.

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Section: Methodsmentioning

confidence: 99%

HIF Stabilization Weakens Primary Cilia

Resnick

2016

PLoS ONE

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“…Another avenue for extension of our results lie with the boundary conditions at the basal end, that is, how to account for the basal body. A growing body of results (12,13,15,21) focus on the basal body both as a modifier of the mechanical response and as some sort of 'gate' regulating the transport of materials in and out of the cilioplasm, thus the basal body potentially serves as the site of cellular flow sensing. We have demonstrated the possibility of investigating basal body dynamics by observing ciliary dynamics.…”

Section: Resultsmentioning

confidence: 99%

“…Our experimental protocols for the growth, maintainance, and pharmacological manipulations of ciliated epithelial cells and optical trapping of cilia have been published elsewhere (15,20,22), so here we only provide a brief summary. Conditionally immortalized epithelial cells originally microdissected from the cortical collecting duct of an Immortomouse are grown to confluence and allowed to differentiate for several days, during which time a cilium emerges.…”

Section: Methodsmentioning

confidence: 99%

“…In this section, we provide the results of several approaches that attempt to explain the apparent length dependence of EI e f f . Following (14,15,17), we initially modeled the cilium as a uniform cantilevered beam of length 'L' subject to external loading. This 'elastica' model for a primary cilium treats the structure as a homogeneous isotropic flexible cylindrical beam with a hemispherical endcap, constrained at the basal end and free to move at the distal end.…”

Section: Theoretical Analysismentioning

confidence: 99%

“…The most general case of an end connected to a translational and rotatory spring, linear and torsional damper, and mass with rotational inertia is covered in (43). While boundary conditions for the basal attachment of cilia are not yet fully known, preliminary results (15,16,21) have shown that the fixed end is neither free, clamped nor hinged. One current model treats the fixed end as constrained by a nonlinear rotatory spring obeying a force law F(θ) = Jθ + αθ 2 (15,16), where 'J' is the linear (Hookean) spring constant and 'α' the nonlinear coefficient, while another incorporates a viscoelastic rotatory spring (21).…”

Section: Generalized Cantilevered Beammentioning

confidence: 99%

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Mechanical Properties of a Primary Cilium from the Stochastic Motions of the Cilium Tip

Resnick

Feng

Peng

et al. 2018

Preprint

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The stochastic tip dynamics of a primary cilium held within an optical trap is quantified by combining experimental, analytical and computational tools. Primary cilia are cellular organelles, present on most vertebrate cells, hypothesized to function as a fluid flow sensor. The mechanical properties of a cilium remain incompletely characterized. We measured the fluctuating position of an optically trapped cilium tip under untreated, Taxol-treated, and HIF-stabilized conditions. We applied analytical modeling to derive the mean-squared displacement of the trapped tip of a cilium and compared the results with experimental measurements. We provide, for the first time, evidence that the effective flexural rigidity of a ciliary axoneme is length-dependent, and longer cilia are stiffer than shorter cilia. We then provide a rational explanation for both effects. We demonstrate that the apparent length-dependent flexural rigidity can be understood by a combination of modeling axonemal microtubules orthotropic elastic shells and including (actin-driven) active stochastic basal body motion. It is hoped that our improved characterization of cilia will result in deeper understanding of the biological function of cellular flow sensing by this organelle. Our model could be profitably applied to motile cilia and our results also demonstrate the possibility of using easily observable ciliary dynamics to probe interior cytoskeletal dynamics. Experimental RationaleHere, we consider the primary cilium as a passive mechanical beam capable of transducing kinetic energy of flowing fluid into elastic strain (bending) energy. Bending the cilium seems to be required to initiate calcium signaling (2), and the amount of bending in response to applied flow can be characterized by the flexural rigidity (equivalently, bending modulus) (14) 'EI'. Even so, the mechanical response of primary cilia to external loading remains incompletely characterized (15). Most prior measurements of the ciliary bending modulus fall within the range of 10-50 pN*µm 2 (14), (16), but there are also measurements that report significantly higher bending modulus, as high as 300 pN*µm 2 (17). As we will show and discuss, our results potentially resolve this discrepancy but also raise important new questions. It is essential to note that prior to this report, all reported measurements of the ciliary bending modulus, with the excepton of (15), calculate the bending modulus based on fitting an image of a bent cilium to the equation for a homogeneous cantilevered beam (discussed below, in 'Analysis'). Our approach is qualitatively different and does not rely on imaging the cilium.Measuring the strained position of the cilium tip provides information about the mechanical response of the cilium to an applied mechanical load. For example, subjecting a uniform cantilever of length 'L' to a static load 'q' localized to the free end results in a static tip displacement y = q L 3 /3EI. When both L and y are known, the expression can be inverted to calculate an 'effective' bendin...

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The Role of the Primary Cilium in Cellular Mechanotransduction

Eichholz

Hoey

2016

Mechanobiology

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Mechanical Properties of a Primary Cilium As Measured by Resonant Oscillation

Cited by 22 publications

References 58 publications

HIF Stabilization Weakens Primary Cilia

HIF Stabilization Weakens Primary Cilia

Mechanical Properties of a Primary Cilium from the Stochastic Motions of the Cilium Tip

The Role of the Primary Cilium in Cellular Mechanotransduction

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