Matrix stiffness-modulated proliferation and secretory function of the airway smooth muscle cells.
Multiple pulmonary conditions are characterized by an abnormal misbalance between various tissue components, for example, an increase in the fibrous connective tissue and loss/increase in extracellular matrix proteins (ECM). Such tissue remodeling may adversely impact physiological function of airway smooth muscle cells (ASMCs) responsible for contraction of airways and release of a variety of bioactive molecules. However, few efforts have been made to understand the potentially significant impact of tissue remodeling on ASMCs. Therefore, this study reports how ASMCs respond to a change in mechanical stiffness of a matrix, to which ASMCs adhere because mechanical stiffness of the remodeled airways is often different from the physiological stiffness. Accordingly, using atomic force microscopy (AFM) measurements, we found that the elastic modulus of the mouse bronchus has an arithmetic mean of 23.1 ± 14 kPa (SD) (median 18.6 kPa). By culturing ASMCs on collagen-conjugated polyacrylamide hydrogels with controlled elastic moduli, we found that gels designed to be softer than average airway tissue significantly increased cellular secretion of vascular endothelial growth factor (VEGF). Conversely, gels stiffer than average airways stimulated cell proliferation, while reducing VEGF secretion and agonist-induced calcium responses of ASMCs. These dependencies of cellular activities on elastic modulus of the gel were correlated with changes in the expression of integrin-β1 and integrin-linked kinase (ILK). Overall, the results of this study demonstrate that changes in matrix mechanics alter cell proliferation, calcium signaling, and proangiogenic functions in ASMCs.
Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois;
Artem
A
Shkumatov
Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota;
Michael
M
Thompson
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
Kyoung M
KM
Choi
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
Delphine
D
Sicard
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois;
Kwanghyun
K
Baek
Korea Institute of Industrial Technology, Ansan-si, South Korea;
Dong Hyun
DH
Kim
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
Daniel J
DJ
Tschumperlin
Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota;
Y S
YS
Prakash
Departments of Chemical and Biomolecular Engineering, Pathobiology, and Bioengineering, Institute of Genomic Biology, Univeristy of Illinois at Urbana-Champaign, Urbana, Illinois; and Deptartment of Chemical Engineering, Soongshil University, Seoul, Korea hjkong06@illinois.edu.
Hyunjoon
H
Kong
D008841:Actin Cytoskeleton / Q000378:metabolism; D000403:Airway Resistance; D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D003470:Culture Media; D055119:Elastic Modulus; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008168:Lung / Q000502:physiology / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000502:physiology* / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D003470:Culture Media; D019012:Integrin beta1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
airways smooth muscle cells; asthma; hydrogel; integrin; matrix stiffness