TY - JOUR
T1 - Endothelial cells enhance adipose mesenchymal stromal cell-mediated matrix contraction via ALK receptors and reduced follistatin
T2 - Potential role of endothelial cells in skin fibrosis
AU - Monsuur, Hanneke N.
AU - van den Broek, Lenie J.
AU - Koolwijk, Pieter
AU - Niessen, Frank B.
AU - Gibbs, Susan
PY - 2018/10
Y1 - 2018/10
N2 - Abnormal cutaneous wound healing can lead to formation of fibrotic hypertrophic scars. Although several clinical risk factors have been described, the cross-talk between different cell types resulting in hypertrophic scar formation is still poorly understood. The aim of this in vitro study was to investigate whether endothelial cells (EC) may play a role in skin fibrosis, for example, hypertrophic scar formation after full-thickness skin trauma. Using a collagen/elastin matrix, we developed an in vitro fibrosis model to study the interaction between EC and dermal fibroblasts or adipose tissue-derived mesenchymal stromal cells (ASC). Tissue equivalents containing dermal fibroblasts and EC displayed a normal phenotype. In contrast, tissue equivalents containing ASC and EC displayed a fibrotic phenotype indicated by contraction of the matrix, higher gene expression of ACTA2, COL1A, COL3A, and less secretion of follistatin. The contraction was in part mediated via the TGF-β pathway, as both inhibition of the ALK4/5/7 receptors and the addition of recombinant follistatin resulted in decreased matrix contraction (75±11% and 24±8%, respectively). In conclusion, our study shows that EC may play a critical role in fibrotic events, as seen in hypertrophic scars, by stimulating ASC-mediated matrix contraction via regulation of fibrosis-related proteins.
AB - Abnormal cutaneous wound healing can lead to formation of fibrotic hypertrophic scars. Although several clinical risk factors have been described, the cross-talk between different cell types resulting in hypertrophic scar formation is still poorly understood. The aim of this in vitro study was to investigate whether endothelial cells (EC) may play a role in skin fibrosis, for example, hypertrophic scar formation after full-thickness skin trauma. Using a collagen/elastin matrix, we developed an in vitro fibrosis model to study the interaction between EC and dermal fibroblasts or adipose tissue-derived mesenchymal stromal cells (ASC). Tissue equivalents containing dermal fibroblasts and EC displayed a normal phenotype. In contrast, tissue equivalents containing ASC and EC displayed a fibrotic phenotype indicated by contraction of the matrix, higher gene expression of ACTA2, COL1A, COL3A, and less secretion of follistatin. The contraction was in part mediated via the TGF-β pathway, as both inhibition of the ALK4/5/7 receptors and the addition of recombinant follistatin resulted in decreased matrix contraction (75±11% and 24±8%, respectively). In conclusion, our study shows that EC may play a critical role in fibrotic events, as seen in hypertrophic scars, by stimulating ASC-mediated matrix contraction via regulation of fibrosis-related proteins.
KW - Endothelial cells
KW - Fibrosis
KW - Scar
KW - Skin
UR - http://www.scopus.com/inward/record.url?scp=85046683880&partnerID=8YFLogxK
U2 - 10.1002/jcp.26494
DO - 10.1002/jcp.26494
M3 - Article
C2 - 29345319
AN - SCOPUS:85046683880
VL - 233
SP - 6714
EP - 6722
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
SN - 0021-9541
IS - 10
ER -