Human cardiac fibroblasts adaptive responses to controlled combined mechanical strain and oxygen changes in vitro.
Upon cardiac pathological conditions such as ischemia, microenvironmental changes instruct a series of cellular responses that trigger cardiac fibroblasts-mediated tissue adaptation and inflammation. A comprehensive model of how early environmental changes may induce cardiac fibroblasts (CF) pathological responses is far from being elucidated, partly due to the lack of approaches involving complex and simultaneous environmental stimulation. Here, we provide a first analysis of human primary CF behavior by means of a multi-stimulus microdevice for combined application of cyclic mechanical strain and controlled oxygen tension. Our findings elucidate differential human CFs responses to different combinations of the above stimuli. Individual stimuli cause proliferative effects (PHH3+mitotic cells, YAP translocation, PDGF secretion) or increase collagen presence. Interestingly, only the combination of hypoxia and a simulated loss of contractility (2% strain) is able to additionally induce increased CF release of inflammatory and pro-fibrotic cytokines and matrix metalloproteinases.
Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
Giovanni Stefano
0000-0003-4775-6676
GS
Ugolini
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.|Biosym IRG, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
Andrea
0000-0003-2777-1043
A
Pavesi
Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
Marco
M
Rasponi
Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
Gianfranco Beniamino
GB
Fiore
Biosym IRG, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States.
Roger
R
Kamm
Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
Monica
0000-0001-8607-7196
M
Soncini
D000222:Adaptation, Physiological; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003584:Cytological Techniques / Q000295:instrumentation; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D013314:Stress, Mechanical; D013312:Stress, Physiological
D016207:Cytokines; D003094:Collagen; D010100:Oxygen
cardiac fibroblasts; cardiac remodeling; human; human biology; medicine; organs-on-chip; pathological modeling