Material-driven fibronectin assembly rescues matrix defects due to mutations in collagen IV in fibroblasts
| Autor: | Andrés J. García, Dennis W. Zhou, Manuel Salmerón-Sánchez, Tom Van Agtmael, Yinhui Lu, Lauren Fleming, Elie Ngandu Mpoyi, Karl E. Kadler, Yuan Yan Sin, Marco Cantini, Mercedes Costell |
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| Rok vydání: | 2020 |
| Předmět: |
Collagen Type IV
Cell signaling Population Integrin Biophysics Bioengineering 02 engineering and technology Matrix (biology) medicine.disease_cause Basement Membrane Article Biomaterials Extracellular matrix 03 medical and health sciences 0302 clinical medicine Laminin medicine Extracellular Humans education Cell adhesion 030304 developmental biology education.field_of_study 0303 health sciences Mutation biology Chemistry Endoplasmic reticulum Fibroblasts 021001 nanoscience & nanotechnology Phenotype Extracellular Matrix Fibronectins Cell biology Fibronectin Mechanics of Materials Ceramics and Composites biology.protein 0210 nano-technology 030217 neurology & neurosurgery |
| Zdroj: | Biomaterials |
| ISSN: | 0142-9612 |
| DOI: | 10.1016/j.biomaterials.2020.120090 |
| Popis: | 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 β(1)-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. |
| Databáze: | OpenAIRE |
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