An engineered, quantifiable in vitro model for analysing the effect of proteostasis-targeting drugs on tissue physical properties.
Détails
ID Serval
serval:BIB_78ACC158B294
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
An engineered, quantifiable in vitro model for analysing the effect of proteostasis-targeting drugs on tissue physical properties.
Périodique
Biomaterials
ISSN
1878-5905 (Electronic)
ISSN-L
0142-9612
Statut éditorial
Publié
Date de publication
11/2018
Peer-reviewed
Oui
Volume
183
Pages
102-113
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Cellular function depends on the maintenance of protein homeostasis (proteostasis) by regulated protein degradation. Chronic dysregulation of proteostasis is associated with neurodegenerative and age-related diseases, and drugs targeting components of the protein degradation apparatus are increasingly used in cancer therapies. However, as chronic imbalances rather than loss of function mediate their pathogenesis, research models that allow for the study of the complex effects of drugs on tissue properties in proteostasis-associated diseases are almost completely lacking. Here, to determine the functional effects of impaired proteostatic fine-tuning, we applied a combination of materials science characterisation techniques to a cell-derived, in vitro model of bone-like tissue formation in which we pharmacologically perturbed protein degradation. We show that low-level inhibition of VCP/p97 and the proteasome, two major components of the degradation machinery, have remarkably different effects on the bone-like material that human bone-marrow derived mesenchymal stromal cells (hMSC) form in vitro. Specifically, whilst proteasome inhibition mildly enhances tissue formation, Raman spectroscopic, atomic force microscopy-based indentation, and electron microscopy imaging reveal that VCP/p97 inhibition induces the formation of bone-like tissue that is softer, contains less protein, appears to have more crystalline mineral, and may involve aberrant micro- and ultra-structural tissue organisation. These observations contrast with findings from conventional osteogenic assays that failed to identify any effect on mineralisation. Taken together, these data suggest that mild proteostatic impairment in hMSC alters the bone-like material they form in ways that could explain some pathologies associated with VCP/p97-related diseases. They also demonstrate the utility of quantitative materials science approaches for tackling long-standing questions in biology and medicine, and could form the basis for preclinical drug testing platforms to develop therapies for diseases stemming from perturbed proteostasis or for cancer therapies targeting protein degradation. Our findings may also have important implications for the field of tissue engineering, as the manufacture of cell-derived biomaterial scaffolds may need to consider proteostasis to effectively replicate native tissues.
Mots-clé
Biophysical Phenomena, Bone Regeneration/drug effects, Cell Culture Techniques, Cell Differentiation, Cell Line, Tumor, Drug Development, Humans, Mesenchymal Stem Cells/drug effects, Mesenchymal Stem Cells/metabolism, Osteoblasts/drug effects, Osteoblasts/metabolism, Proteasome Endopeptidase Complex/metabolism, Proteolysis/drug effects, Proteostasis/drug effects, Tissue Engineering/methods, Tissue Scaffolds/chemistry, Valosin Containing Protein/antagonists & inhibitors, Atomic force microscopy, Cancer diagnosis and therapy, Proteasome, Proteostasis, Raman spectroscopy, VCP/p97
Pubmed
Web of science
Open Access
Oui
Création de la notice
12/01/2024 10:14
Dernière modification de la notice
03/12/2024 15:46