Primary cilia mechanics affects cell mechanosensation: A computational study

Khayyeri, Hanifeh; Barreto, Sara; Lacroix, Damien

doi:10.1016/j.jtbi.2015.04.034

Cited by 35 publications

(37 citation statements)

References 56 publications

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“…In the case of the two integrins that we tested, beta 1 and beta 3, the response pattern to flow were found to be different between IS cells and controls. These trends further demonstrate the existence of an altered mechanosensation in IS cells, and reflect the in silico work of Khayyeri et al 11,. where elongated cilia were modeled to show hypersensitivity to mechanical stimuli.…”

Section: Discussionsupporting

confidence: 87%

Identification of Elongated Primary Cilia with Impaired Mechanotransduction in Idiopathic Scoliosis Patients

Oliazadeh

Gorman

Eveleigh

et al. 2017

Sci Rep

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The primary cilium is an outward projecting antenna-like organelle with an important role in bone mechanotransduction. The capacity to sense mechanical stimuli can affect important cellular and molecular aspects of bone tissue. Idiopathic scoliosis (IS) is a complex pediatric disease of unknown cause, defined by abnormal spinal curvatures. We demonstrate significant elongation of primary cilia in IS patient bone cells. In response to mechanical stimulation, these IS cells differentially express osteogenic factors, mechanosensitive genes, and signaling genes. Considering that numerous ciliary genes are associated with a scoliosis phenotype, among ciliopathies and knockout animal models, we expected IS patients to have an accumulation of rare variants in ciliary genes. Instead, our SKAT-O analysis of whole exomes showed an enrichment among IS patients for rare variants in genes with a role in cellular mechanotransduction. Our data indicates defective cilia in IS bone cells, which may be linked to heterogeneous gene variants pertaining to cellular mechanotransduction.

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Section: Discussionsupporting

confidence: 87%

Identification of Elongated Primary Cilia with Impaired Mechanotransduction in Idiopathic Scoliosis Patients

Oliazadeh

Gorman

Eveleigh

et al. 2017

Sci Rep

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“…The membrane of the cilia contains several cilia-specific receptors such as ion channels and signaling molecules that serve to receive signals from the environment in order to produce an appropriate response 15 . Primary cilia have been shown to transmit signals to the cytoskeleton and other cellular organelles that regulate the cells' mechanoresponse in a manner dependent on the cilia length 26 . The elongation of the primary cilia has been shown to increase the mechanosensitivity of cells to signals and has been found as a biomarker of alterations in cellular homeostasis 19,26,27 .…”

Section: Hypoxia Inhibits Primary Cilia Formation and Reduces Cell-mementioning

confidence: 99%

“…Primary cilia have been shown to transmit signals to the cytoskeleton and other cellular organelles that regulate the cells' mechanoresponse in a manner dependent on the cilia length 26 . The elongation of the primary cilia has been shown to increase the mechanosensitivity of cells to signals and has been found as a biomarker of alterations in cellular homeostasis 19,26,27 . In the current study, cells under hypoxic conditions revealed a significantly lower percentage of elongated cilia than those seen in normoxia.…”

Section: Hypoxia Inhibits Primary Cilia Formation and Reduces Cell-mementioning

confidence: 99%

Hypoxia inhibits primary cilia formation and reduces cell-mediated contraction in stress-deprived rat tail tendon fascicles

Lavagnino

Oslapas

Gardner

et al. 2016

MLTJ

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SummaryBackground: Hypoxia, which is associated with chronic tendinopathy, has recently been shown to decrease the mechanosensitivity of some cells. Therefore, the purpose of this study was to determine the effect of hypoxia on the formation of elongated primary cilia (a mechanosensing organelle of tendon cells) in vitro and to determine the effect of hypoxia on cell-mediated contraction of stress-deprived rat tail tendon fascicles (RTTfs). Methods: Tendon cells isolated from RTTfs were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions for 24 hours. The cells were then stained for tubulin and the number of cells with elongated cilia counted. RTTfs from 1-month-old male Sprague-Dawley rats were also cultured under hypoxic and normoxic conditions for three days and tendon length measured daily. Results: A significant (p=0.002) decrease in the percent of elongated cilia was found in cells maintained in hypoxic conditions (54.1%±12.2) when compared in normoxic conditions (71.7%±6.32). RTTfs in hypoxia showed a significant decrease in the amount of contraction compared to RTTfs in normoxia after two (p=0.007) and three (p=0.001) days. Conclusion:The decreased incidence of elongated primary cilia in a hypoxic environment, as well as the decreased mechanoresponsiveness of tendon cells under these conditions may relate to the inability of some cases of chronic tendinopathy to respond to strain-based rehabilitation modalities (i.e. eccentric loading).

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“…Further efforts to model the mechanical deformation of the cilia have mapped the areas of predicted strain. These computational studies have provided some insight into the likely localization of mechanosensitive protein structures and how the architecture of the cilium may affect transduction of signals from the surrounding environment . There is a substantial body of work that loss of cilia in both experimental models and naturally occurring genetic mutations and ciliopathic diseases leads to reduced cellular mechanosensitivity and thus affects tissue homeostasis.…”

Section: Mechanotransduction Pathways: Mechanosensory Complex and Sigmentioning

confidence: 99%

Key developments that impacted the field of mechanobiology and mechanotransduction

Wall

Butler

Haj

et al. 2017

Journal Orthopaedic Research

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Advances in mechanobiology have evolved through insights from multiple disciplines including structural engineering, biomechanics, vascular biology, and orthopaedics. In this paper, we reviewed the impact of key reports related to the study of applied loads on tissues and cells and the resulting signal transduction pathways. We addressed how technology has helped advance the burgeoning field of mechanobiology (over 33,600 publications from 1970 to 2016). We analyzed the impact of critical ideas and then determined how these concepts influenced the mechanobiology field by looking at the citation frequency of these reports as well as tracking how the overall number of citations within the field changed over time. These data allowed us to understand how a key publication, idea, or technology guided or enabled the field. Initial observations of how forces acted on bone and soft tissues stimulated the development of computational solutions defining how forces affect tissue modeling and remodeling. Enabling technologies, such as cell and tissue stretching, compression, and shear stress devices, allowed more researchers to explore how deformation and fluid flow affect cells. Observation of the cell as a tensegrity structure and advanced methods to study genetic regulation in cells further advanced knowledge of specific mechanisms of mechanotransduction. The future of the field will involve developing gene and drug therapies to simulate or augment beneficial load regimens in patients and in mechanically conditioning organs for implantation. Here, we addressed a history of the field, but we limited our discussions to advances in musculoskeletal mechanobiology, primarily in bone, tendon, and ligament tissues. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:605-619, 2018.

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Primary cilia mechanics affects cell mechanosensation: A computational study

Cited by 35 publications

References 56 publications

Identification of Elongated Primary Cilia with Impaired Mechanotransduction in Idiopathic Scoliosis Patients

Identification of Elongated Primary Cilia with Impaired Mechanotransduction in Idiopathic Scoliosis Patients

Hypoxia inhibits primary cilia formation and reduces cell-mediated contraction in stress-deprived rat tail tendon fascicles

Key developments that impacted the field of mechanobiology and mechanotransduction

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