TY - JOUR
T1 - Delineating cooperative effects of Notch and biomechanical signals on patterned liver differentiation
AU - Jain, Ishita
AU - Berg, Ian C.
AU - Acharya, Ayusha
AU - Blaauw, Maddie
AU - Gosstola, Nicholas
AU - Perez-Pinera, Pablo
AU - Underhill, Gregory H.
N1 - Funding Information:
This work was supported by the National Institutes of Health (R01DK125471 to GHU). The authors acknowledge Helene Strick-Marchand and Mary C Weiss (Institut Pasteur) for providing BMEL cells. The authors also thank the Institute of Genomic Biology’s core facility at the University of Illinois at Urbana-Champaign for their assistance with the microscopy performed in these studies.
Funding Information:
This work was supported by the National Institutes of Health (R01DK125471 to GHU). The authors acknowledge Helene Strick-Marchand and Mary C Weiss (Institut Pasteur) for providing BMEL cells. The authors also thank the Institute of Genomic Biology’s core facility at the University of Illinois at Urbana-Champaign for their assistance with the microscopy performed in these studies.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Controlled in vitro multicellular culture systems with defined biophysical microenvironment have been used to elucidate the role of Notch signaling in the spatiotemporal regulation of stem and progenitor cell differentiation. In addition, computational models incorporating features of Notch ligand-receptor interactions have provided important insights into Notch pathway signaling dynamics. However, the mechanistic relationship between Notch-mediated intercellular signaling and cooperative microenvironmental cues is less clear. Here, liver progenitor cell differentiation patterning was used as a model to systematically evaluate the complex interplay of cellular mechanics and Notch signaling along with identifying combinatorial mechanisms guiding progenitor fate. We present an integrated approach that pairs a computational intercellular signaling model with defined microscale culture configurations provided within a cell microarray platform. Specifically, the cell microarray-based experiments were used to validate and optimize parameters of the intercellular Notch signaling model. This model incorporated the experimentally established multicellular dimensions of the cellular microarray domains, mechanical stress-related activation parameters, and distinct Notch receptor-ligand interactions based on the roles of the Notch ligands Jagged-1 and Delta-like-1. Overall, these studies demonstrate the spatial control of mechanotransduction-associated components, key growth factor and Notch signaling interactions, and point towards a possible role of E-Cadherin in translating intercellular mechanical gradients to downstream Notch signaling.
AB - Controlled in vitro multicellular culture systems with defined biophysical microenvironment have been used to elucidate the role of Notch signaling in the spatiotemporal regulation of stem and progenitor cell differentiation. In addition, computational models incorporating features of Notch ligand-receptor interactions have provided important insights into Notch pathway signaling dynamics. However, the mechanistic relationship between Notch-mediated intercellular signaling and cooperative microenvironmental cues is less clear. Here, liver progenitor cell differentiation patterning was used as a model to systematically evaluate the complex interplay of cellular mechanics and Notch signaling along with identifying combinatorial mechanisms guiding progenitor fate. We present an integrated approach that pairs a computational intercellular signaling model with defined microscale culture configurations provided within a cell microarray platform. Specifically, the cell microarray-based experiments were used to validate and optimize parameters of the intercellular Notch signaling model. This model incorporated the experimentally established multicellular dimensions of the cellular microarray domains, mechanical stress-related activation parameters, and distinct Notch receptor-ligand interactions based on the roles of the Notch ligands Jagged-1 and Delta-like-1. Overall, these studies demonstrate the spatial control of mechanotransduction-associated components, key growth factor and Notch signaling interactions, and point towards a possible role of E-Cadherin in translating intercellular mechanical gradients to downstream Notch signaling.
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U2 - 10.1038/s42003-022-03840-9
DO - 10.1038/s42003-022-03840-9
M3 - Article
C2 - 36207581
AN - SCOPUS:85139571681
VL - 5
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 1073
ER -