Mallikarjun, V, Dobre, O, Jackson, M, Kidd, M, Llewellyn, J, Gilbert, HTJ, Richardson, S and Swift, J (2022) Loss of cytoskeletal proteostasis links dysregulation of cell size and mechanotransduction in mesenchymal stem cell senescence. arxiv.

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<h4>ABSTRACT</h4> Tissues are maintained by homeostatic feedback mechanisms where cells respond to, but also modify, the chemical and mechanical properties of the surrounding extracellular matrix. Mesenchymal stem cells (MSCs) resident in the marrow niche experience a diverse mechanical environment, but ageing can affect the composition and quality of bone and marrow tissues. Here we quantified the effect of replication-induced senescence on MSC morphology and their ability to correctly respond to different substrate stiffnesses. The matrix proteome was found to be sensitive to substrate stiffness, but pharmacological inhibition of cellular contractility perturbed this response, decreasing levels of tenascin-C, fibulins and fibronectin. Similar decreases in these mechanosensitive proteins were observed in senescent cells, suggested a decoupling of mechanotransduction pathways. Intracellular proteomic and transcriptomic analyses confirmed a decrease in components of the cytoskeletal chaperone complex CCT/TRiC in senescent MSCs. Finally, pharmacological inhibition of CCT/TRiC was able to partially recapitulate senescence-associated morphological changes in non-senescent MSCs. These results demonstrate a senescence-mediated perturbation to cytoskeletal homeostasis, pathways of mechanotransduction and the secretion of matrix proteins required for tissue maintenance.

Item Type: Article
Additional Information: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC925 Diseases of the musculoskeletal system
Divisions: Faculty of Natural Sciences > School of Life Sciences
Depositing User: Symplectic
Date Deposited: 10 Nov 2022 08:56
Last Modified: 10 Nov 2022 08:56

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