An engineered, quantifiable in vitro model for analysing the effect of proteostasis-targeting drugs on tissue physical properties

Biomaterials
Sandra LoaizaHolger W Auner

Abstract

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 indenta...Continue Reading

Citations

Dec 27, 2019·American Journal of Physiology. Cell Physiology·Paula Saavedra-GarcíaHolger W Auner
Jan 17, 2020·Advanced Healthcare Materials·Christoph SalzlechnerEileen Gentleman
Feb 19, 2021·Cellular and Molecular Life Sciences : CMLS·Sinan XiongJianbiao Zhou
Apr 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Paula Saavedra-GarcíaHolger W Auner

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Methods Mentioned

BETA
atomic
electron microscopy
glycosylation
AFM
scanning electron microscopy
imaging techniques
PCR
electrophoresis
Assay

Software Mentioned

CELLQUEST
Image J
GraphPad Prism
GraphPad
JPK SPM
SPSS

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