Material-driven fibronectin assembly rescues matrix defects due to mutations in collagen IV in fibroblasts

Ngandu Mpoyi, E. et al. (2020) Material-driven fibronectin assembly rescues matrix defects due to mutations in collagen IV in fibroblasts. Biomaterials, 252, 120090. (doi: 10.1016/j.biomaterials.2020.120090) (PMID:32413593)

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Abstract

Basement membranes (BMs) are specialised extracellular matrices that provide structural support to tissues as well as influence cell behaviour and signalling. Mutations in COL4A1/COL4A2, a major BM component, cause a familial form of eye, kidney and cerebrovascular disease, including stroke, while common variants in these genes are a risk factor for intracerebral haemorrhage in the general population. These phenotypes are associated with matrix defects, due to mutant protein incorporation in the BM and/or its absence by endoplasmic reticulum (ER) retention. However, the effects of these mutations on matrix stiffness, the contribution of the matrix to the disease mechanism(s) and its effects on the biology of cells harbouring a collagen IV mutation remain poorly understood. To shed light on this, we employed synthetic polymer biointerfaces, poly(ethyl acrylate) (PEA) and poly(methyl acrylate) (PMA) coated with ECM proteins laminin or fibronectin (FN), to generate controlled microenvironments and investigate their effects on the cellular phenotype of primary fibroblasts harbouring a COL4A2+/G702D mutation. FN nanonetworks assembled on PEA induced increased deposition and assembly of collagen IV in COL4A2+/G702D cells, which was associated with reduced ER size and enhanced levels of protein chaperones such as BIP, suggesting increased protein folding capacity of the cell. FN nanonetworks on PEA also partially rescued the reduced stiffness of the deposited matrix and cells, and enhanced cell adhesion through increased actin-myosin contractility, effectively rescuing some of the cellular phenotypes associated with COL4A1/4A2 mutations. The mechanism by which FN nanonetworks enhanced the cell phenotype involved integrin β1-mediated signalling. Collectively, these results suggest that biomaterials and enhanced integrin signalling via assembled FN are able to shape the matrix and cellular phenotype of the COL4A2+/G702D mutation in patient-derived cells.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Salmeron-Sanchez, Professor Manuel and Sin, Dr Angie and Ngandu Mpoyi, Elie and Fleming, Lauren and Van Agtmael, Dr Tom and Cantini, Dr Marco
Authors: Ngandu Mpoyi, E., Cantini, M., Sin, Y. Y., Fleming, L., Zhou, D. W., Costell, M., Lu, Y., Kadler, K., García, A. J., Van Agtmael, T., and Salmeron-Sanchez, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Biomaterials
Publisher:Elsevier
ISSN:0142-9612
ISSN (Online):1878-5905
Published Online:03 May 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Biomaterials 252: 120090
Publisher Policy:Reproduced under a Creative Commons License
Related URLs:
Data DOI:10.5525/gla.researchdata.720

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173192Engineering growth factor microenvironments- a new therapeutic paradigm for regenerative medicineManuel Salmeron-SanchezEngineering and Physical Sciences Research Council (EPSRC)EP/P001114/1ENG - Biomedical Engineering
161012DTC in cell and proteomic technologies (continuation)Jonathan CooperEngineering and Physical Sciences Research Council (EPSRC)EP/F500424/1ENG - Biomedical Engineering
303613Engineered microenvironments to harvest stem cell response to viscosity for cartilage repairMarco CantiniMedical Research Council (MRC)MR/S005412/1ENG - Biomedical Engineering
302164Collagen IV variants and their role in intracerebral haemorrhage in the general populationTom Van AgtmaelMedical Research Council (MRC)MR/R005567/1CAMS - Cardiovascular Science
167056Elucidation of molecular pathways underlying renal disease caused by Co/4a 1 mutations using mouse models.Tom Van AgtmaelKidney Research UK (KIDNEYRE)RP19/2012Institute of Cardiovascular & Medical Sciences