Material-driven fibronectin assembly rescues matrix defects due to mutations in collagen IV in fibroblasts
Source: https://eprints.gla.ac.uk/208477/ Parent: https://eprints.gla.ac.uk/view/project_code/303613.html
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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: | Fleming, Lauren and Salmeron-Sanchez, Professor Manuel and Sin, Dr Angie and Ngandu Mpoyi, Elie and Van Agtmael, Professor 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 > School of Cardiovascular & Metabolic Health 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: | - Author |
| Data DOI: | 10.5525/gla.researchdata.720 |
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Funder and Project Information
Funder and Project Information
Funder and Project Information
Project Code
Award No
Project Name
Principal Investigator
Funder's Name
Funder Ref
Lead Dept
Engineering growth factor microenvironments- a new therapeutic paradigm for regenerative medicine
Manuel Salmeron-Sanchez
Engineering and Physical Sciences Research Council (EPSRC)
EP/P001114/1
ENG - Biomedical Engineering
DTC in cell and proteomic technologies (continuation)
Jonathan Cooper
Engineering and Physical Sciences Research Council (EPSRC)
EP/F500424/1
ENG - Biomedical Engineering
Engineered microenvironments to harvest stem cell response to viscosity for cartilage repair
Marco Cantini
Medical Research Council (MRC)
MR/S005412/1
ENG - Biomedical Engineering
Collagen IV variants and their role in intracerebral haemorrhage in the general population
Tom Van Agtmael
Medical Research Council (MRC)
MR/R005567/1
CAMS - Cardiovascular Science
Elucidation of molecular pathways underlying renal disease caused by Co/4a 1 mutations using mouse models.
Tom Van Agtmael
RP19/2012
Institute of Cardiovascular & Medical Sciences
Deposit and Record Details
| ID Code: | 208477 |
| Depositing User: | Publications Router |
| Datestamp: | 04 May 2020 15:56 |
| Last Modified: | 29 Oct 2024 13:46 |
| Date of acceptance: | 2 May 2020 |
| Date of first online publication: | 3 May 2020 |
| Date Deposited: | 6 May 2020 |
| Data Availability Statement: | Yes |
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