TY - JOUR
T1 - Cyclic strain has antifibrotic effects on the human cardiac fibroblast transcriptome in a human cardiac fibrosis-on-a-chip platform
AU - Bracco Gartner, Tom C.L.
AU - Wang, Ye
AU - Leiteris, Laurynas
AU - van Adrichem, Iris
AU - Marsman, Judith
AU - Goumans, Marie José
AU - Bouten, Carlijn V.C.
AU - Sluijter, Joost P.G.
AU - den Toonder, Jaap M.J.
AU - Suyker, Willem J.L.
AU - Hjortnaes, Jesper
N1 - Publisher Copyright:
© 2023
PY - 2023/8
Y1 - 2023/8
N2 - In cardiac fibrosis, in response to stress or injury, cardiac fibroblasts deposit excessive amounts of collagens which contribute to the development of heart failure. The biochemical stimuli in this process have been extensively studied, but the influence of cyclic deformation on the fibrogenic behavior of cardiac fibroblasts in the ever-beating heart is not fully understood. In fact, most investigated mechanotransduction pathways in cardiac fibroblasts seem to ultimately have profibrotic effects, which leaves an important question in cardiac fibrosis research unanswered: how do cardiac fibroblasts stay quiescent in the ever-beating human heart? In this study, we developed a human cardiac fibrosis-on-a-chip platform and utilized it to investigate if and how cyclic strain affects fibrogenic signaling. The pneumatically actuated platform can expose engineered tissues to controlled strain magnitudes of 0–25% – which covers the entire physiological and pathological strain range in the human heart – and to biochemical stimuli and enables high-throughput screening of multiple samples. Microtissues of human fetal cardiac fibroblasts (hfCF) embedded in gelatin methacryloyl (GelMA) were 3D-cultured on this platform and exposed to strain conditions which mimic the healthy human heart. The results provide evidence of an antifibrotic effect of the applied strain conditions on cardiac fibroblast behavior, emphasizing the influence of biomechanical stimuli on the fibrogenic process and giving a detailed overview of the mechanosensitive pathways and genes involved, which can be used in the development of novel therapies against cardiac fibrosis.
AB - In cardiac fibrosis, in response to stress or injury, cardiac fibroblasts deposit excessive amounts of collagens which contribute to the development of heart failure. The biochemical stimuli in this process have been extensively studied, but the influence of cyclic deformation on the fibrogenic behavior of cardiac fibroblasts in the ever-beating heart is not fully understood. In fact, most investigated mechanotransduction pathways in cardiac fibroblasts seem to ultimately have profibrotic effects, which leaves an important question in cardiac fibrosis research unanswered: how do cardiac fibroblasts stay quiescent in the ever-beating human heart? In this study, we developed a human cardiac fibrosis-on-a-chip platform and utilized it to investigate if and how cyclic strain affects fibrogenic signaling. The pneumatically actuated platform can expose engineered tissues to controlled strain magnitudes of 0–25% – which covers the entire physiological and pathological strain range in the human heart – and to biochemical stimuli and enables high-throughput screening of multiple samples. Microtissues of human fetal cardiac fibroblasts (hfCF) embedded in gelatin methacryloyl (GelMA) were 3D-cultured on this platform and exposed to strain conditions which mimic the healthy human heart. The results provide evidence of an antifibrotic effect of the applied strain conditions on cardiac fibroblast behavior, emphasizing the influence of biomechanical stimuli on the fibrogenic process and giving a detailed overview of the mechanosensitive pathways and genes involved, which can be used in the development of novel therapies against cardiac fibrosis.
KW - Cardiac fibroblast
KW - Disease modeling
KW - Fibrosis
KW - Mechanotransduction
KW - Organ-on-chip technology
UR - http://www.scopus.com/inward/record.url?scp=85163961435&partnerID=8YFLogxK
U2 - 10.1016/j.jmbbm.2023.105980
DO - 10.1016/j.jmbbm.2023.105980
M3 - Article
C2 - 37399762
AN - SCOPUS:85163961435
SN - 1751-6161
VL - 144
JO - Journal of the mechanical behavior of biomedical materials
JF - Journal of the mechanical behavior of biomedical materials
M1 - 105980
ER -