Use of Patterned Collagen Coated Slides to Study Normal and Scleroderma Lung Fibroblast Migration
Author(s)
Type
Journal Article
Abstract
Systemic sclerosis (SSc) is a spreading fibrotic disease affecting the skin and internal organs. We
aimed to model pathogenic fibroblast migration in SSc in order to identify enhancing factors, measure
the effect of migrating cells on underlying extracellular matrix (ECM) and test possible therapeutic
inhibitors. Novel patterned collagen substrates were used to investigate alignment and migration of
skin and lung fibroblasts from SSc patients and healthy controls. Normal lung but not skin fibroblasts
consistently elongated and aligned with underlying collagen and migrated dependent on PDGF or
serum. SSc lung fibroblasts remained growth factor dependent, did not migrate more rapidly and were
less restricted to alignment of the collagen. Multiple collagen proline and lysine-modifying enzymes
were identified in SSc but not control fibroblast extracellular matrix preparations, indicating differential
levels of ECM modification by the diseased cells. Profiling of migrating cells revealed a possible SCF/cKit
paracrine mechanism contributing to migration via a subpopulation of cells. Heparin, which binds
ligands including PDGF and SCF, and imatininib which blocks downstream tyrosine kinase receptors,
both inhibited lung fibroblast migration individually but showed synergy in SSc cells. Pathologic lung
fibroblasts from SSc patients modify ECM during migration but remain growth factor dependent and
sensitive to inhibitors.
aimed to model pathogenic fibroblast migration in SSc in order to identify enhancing factors, measure
the effect of migrating cells on underlying extracellular matrix (ECM) and test possible therapeutic
inhibitors. Novel patterned collagen substrates were used to investigate alignment and migration of
skin and lung fibroblasts from SSc patients and healthy controls. Normal lung but not skin fibroblasts
consistently elongated and aligned with underlying collagen and migrated dependent on PDGF or
serum. SSc lung fibroblasts remained growth factor dependent, did not migrate more rapidly and were
less restricted to alignment of the collagen. Multiple collagen proline and lysine-modifying enzymes
were identified in SSc but not control fibroblast extracellular matrix preparations, indicating differential
levels of ECM modification by the diseased cells. Profiling of migrating cells revealed a possible SCF/cKit
paracrine mechanism contributing to migration via a subpopulation of cells. Heparin, which binds
ligands including PDGF and SCF, and imatininib which blocks downstream tyrosine kinase receptors,
both inhibited lung fibroblast migration individually but showed synergy in SSc cells. Pathologic lung
fibroblasts from SSc patients modify ECM during migration but remain growth factor dependent and
sensitive to inhibitors.
Date Issued
2017-06-01
Date Acceptance
2017-04-13
Citation
Scientific Reports, 2017, 7
ISSN
2045-2322
Publisher
Nature Publishing Group
Journal / Book Title
Scientific Reports
Volume
7
Copyright Statement
This article is licensed under a Creative Commons Attribution 4.0 International
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons license and your intended use is not permitted
by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the
copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
© The Author(s) 2017
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons license and your intended use is not permitted
by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the
copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
© The Author(s) 2017
License URL
Sponsor
Arthritis Research UK
British Lung Foundation
Raynaud's and Scleroderma Association
Grant Number
20719
RG14-10
BR11
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
IDIOPATHIC PULMONARY-FIBROSIS
PLACEBO-CONTROLLED TRIAL
STEM-CELL FACTOR
SYSTEMIC-SCLEROSIS
GROWTH-FACTOR
DOUBLE-BLIND
DISEASE-MECHANISMS
IMATINIB MESYLATE
MAST-CELLS
SKIN
Publication Status
Published
Article Number
2628