TY - JOUR
T1 - Fibrostenotic phenotype of myofibroblasts in crohn's disease is dependent on tissue stiffness and reversed by LOX inhibition
AU - de Bruyn, Jessica R.
AU - van den Brink, Gijs R.
AU - Steenkamer, Jessica
AU - Buskens, Christianne J.
AU - Bemelman, Willem A.
AU - Meisner, Sander
AU - Muncan, Vanesa
AU - te Velde, Anje A.
AU - D'Haens, Geert R.
AU - Wildenberg, Manon E.
PY - 2018
Y1 - 2018
N2 - Background and Aims: Crohn's disease is a chronic inflammatory disorder of the intestine and often leads to fibrosis, characterized by excess extracellular matrix [ECM] deposition, increased tissue stiffness, and stricture formation. Here we evaluated the contribution of myofibroblast-ECM interactions to the development of intestinal fibrosis in Crohn's disease. Methods: Matched primary human myofibroblasts were isolated from stenotic, inflamed and normal-appearing small intestine within the same Crohn's disease patient [n = 10]. Cells were analyzed by gene expression profiling, microscopy and functional assays, including matrix metalloproteinase [MMP] production and ECM contraction. Results: We demonstrated that myofibroblasts isolated from stenotic intestine differed both in phenotype and function from those isolated from purely inflammatory or normal-appearing intestine of the same patient. Stenotic myofibroblasts displayed increased expression of genes associated with ECM modulation and collagen deposition. Upon culture in a fibrotic environment, normal myofibroblasts increased expression of MMPs to counteract the mechanical force exerted by the matrix. Interestingly, stenotic myofibroblasts showed a paradoxical response with decreased expression of MMP3. In addition, stenotic myofibroblasts expressed increased levels of the collagen crosslinking enzyme lysyl oxidase [LOX] and induced significantly more ECM contraction than both normal and inflamed myofibroblasts. Importantly, LOX inhibition completely restored MMP3 activity in stenotic myofibroblasts grown in a fibrotic environment, and prevented excessive ECM contraction. Conclusions: Together these data indicate aberrancies in the myofibroblast-ECM interaction in Crohn's disease, and identify LOX inhibition as a potential anti-fibrotic agent in this condition.
AB - Background and Aims: Crohn's disease is a chronic inflammatory disorder of the intestine and often leads to fibrosis, characterized by excess extracellular matrix [ECM] deposition, increased tissue stiffness, and stricture formation. Here we evaluated the contribution of myofibroblast-ECM interactions to the development of intestinal fibrosis in Crohn's disease. Methods: Matched primary human myofibroblasts were isolated from stenotic, inflamed and normal-appearing small intestine within the same Crohn's disease patient [n = 10]. Cells were analyzed by gene expression profiling, microscopy and functional assays, including matrix metalloproteinase [MMP] production and ECM contraction. Results: We demonstrated that myofibroblasts isolated from stenotic intestine differed both in phenotype and function from those isolated from purely inflammatory or normal-appearing intestine of the same patient. Stenotic myofibroblasts displayed increased expression of genes associated with ECM modulation and collagen deposition. Upon culture in a fibrotic environment, normal myofibroblasts increased expression of MMPs to counteract the mechanical force exerted by the matrix. Interestingly, stenotic myofibroblasts showed a paradoxical response with decreased expression of MMP3. In addition, stenotic myofibroblasts expressed increased levels of the collagen crosslinking enzyme lysyl oxidase [LOX] and induced significantly more ECM contraction than both normal and inflamed myofibroblasts. Importantly, LOX inhibition completely restored MMP3 activity in stenotic myofibroblasts grown in a fibrotic environment, and prevented excessive ECM contraction. Conclusions: Together these data indicate aberrancies in the myofibroblast-ECM interaction in Crohn's disease, and identify LOX inhibition as a potential anti-fibrotic agent in this condition.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85050825060&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29672662
U2 - https://doi.org/10.1093/ecco-jcc/jjy036
DO - https://doi.org/10.1093/ecco-jcc/jjy036
M3 - Article
C2 - 29672662
SN - 1873-9946
VL - 12
SP - 849
EP - 859
JO - Journal of Crohn s & colitis
JF - Journal of Crohn s & colitis
IS - 7
ER -