ORCID Profile
0000-0002-9591-3616
Current Organisations
The University of Auckland
,
Georgetown University
,
Australian National University
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Publisher: Informa UK Limited
Date: 12-03-2021
Publisher: Informa UK Limited
Date: 02-01-2014
Publisher: Cambridge University Press
Date: 31-03-2020
Publisher: Wiley
Date: 04-2006
Publisher: Informa UK Limited
Date: 06-2012
Publisher: Cold Spring Harbor Laboratory
Date: 12-08-2021
DOI: 10.1101/2021.08.12.452439
Abstract: Mechanical stress and the stiffness of the extracellular matrix are key drivers of tissue development and homeostasis. Aberrant mechanosensation is associated with a wide range of pathologies, including diseases such as osteoarthritis. Substrate stiffness is one of the well-known mechanical properties of the matrix that enabled establishing the central dogma of an integrin-mediated mechanotransduction using stem cells. However, how specific cells ‘feel’ or sense substrate stiffness requires further study. The primary cilium is an essential cellular organelle that senses and integrates mechanical and chemical signals from the extracellular environment. We hypothesised that the primary cilium dynamically alters its length and position to fine-tune cell mechanosignalling based on substrate stiffness alone. We used a hydrogel system of varying substrate stiffness to examine the role of substrate stiffness on cilia frequency, length and centriole position as well as cell and nuclei area over time. Contrary to other cell types, we show that chondrocyte primary cilia shorten on softer substrates demonstrating tissue-specific mechanosensing which is aligned with the tissue stiffness the cells originate from. We further show that stiffness alone determines centriole positioning to either the basal or apical membrane during attachment and spreading, with centriole positioned towards the basal membrane on stiffer substrates. These phenomena are mediated by force generation actin-myosin stress fibres in a time-dependent manner. Based on these findings, we propose that substrate stiffness plays a central role in cilia positioning, regulating cellular response to external forces, and may be a key driver of mechanosignalling-associated diseases. The primary cilium has been thrust into the limelight owing to its role as a cellular sensor in embryonic development and adult tissue maintenance. How the primary cilium interacts with the mechanical environment still remains unclear. We show that substrate stiffness dynamically regulates primary cilium length and position through integrin-mediated traction forces, the cilia are a key determinant of cell shape on certain stiffnesses. Our data support the promising potential of primary cilia as a novel target in mechanotherapy for improved clinical outcomes in cartilage pathobiology.
Publisher: Project MUSE
Date: 2012
Publisher: Informa UK Limited
Date: 25-03-2019
Publisher: Informa UK Limited
Date: 03-2009
No related grants have been discovered for Patricia O'Brien.