TY - JOUR
T1 - Microtissue Geometry and Cell-Generated Forces Drive Patterning of Liver Progenitor Cell Differentiation in 3D
AU - Berg, Ian C.
AU - Mohagheghian, Erfan
AU - Habing, Krista
AU - Wang, Ning
AU - Underhill, Gregory H.
N1 - Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2021/6/23
Y1 - 2021/6/23
N2 - 3D microenvironments provide a unique opportunity to investigate the impact of intrinsic mechanical signaling on progenitor cell differentiation. Using a hydrogel-based microwell platform, arrays of 3D, multicellular microtissues in constrained geometries, including toroids and cylinders are produced. These generated distinct mechanical profiles to investigate the impact of geometry and stress on early liver progenitor cell fate using a model liver development system. Image segmentation allows the tracking of individual cell fate and the characterization of distinct patterning of hepatocytic makers to the outer shell of the microtissues, and the exclusion from the inner diameter surface of the toroids. Biliary markers are distributed throughout the interior regions of micropatterned tissues and are increased in toroidal tissues when compared with those in cylindrical tissues. Finite element models of predicted stress distributions, combined with mechanical measurements, demonstrates that intercellular tension correlates with increased hepatocytic fate, while compression correlates with decreased hepatocytic and increased biliary fate. This system, which integrates microfabrication, imaging, mechanical modeling, and quantitative analysis, demonstrates how microtissue geometry can drive patterning of mechanical stresses that regulate cell differentiation trajectories. This approach may serve as a platform for further investigation of signaling mechanisms in the liver and other developmental systems.
AB - 3D microenvironments provide a unique opportunity to investigate the impact of intrinsic mechanical signaling on progenitor cell differentiation. Using a hydrogel-based microwell platform, arrays of 3D, multicellular microtissues in constrained geometries, including toroids and cylinders are produced. These generated distinct mechanical profiles to investigate the impact of geometry and stress on early liver progenitor cell fate using a model liver development system. Image segmentation allows the tracking of individual cell fate and the characterization of distinct patterning of hepatocytic makers to the outer shell of the microtissues, and the exclusion from the inner diameter surface of the toroids. Biliary markers are distributed throughout the interior regions of micropatterned tissues and are increased in toroidal tissues when compared with those in cylindrical tissues. Finite element models of predicted stress distributions, combined with mechanical measurements, demonstrates that intercellular tension correlates with increased hepatocytic fate, while compression correlates with decreased hepatocytic and increased biliary fate. This system, which integrates microfabrication, imaging, mechanical modeling, and quantitative analysis, demonstrates how microtissue geometry can drive patterning of mechanical stresses that regulate cell differentiation trajectories. This approach may serve as a platform for further investigation of signaling mechanisms in the liver and other developmental systems.
KW - 3D cell cultures
KW - liver tissue engineering
KW - mechanobiology
KW - microtissues
KW - microwells
UR - http://www.scopus.com/inward/record.url?scp=85104618928&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104618928&partnerID=8YFLogxK
U2 - 10.1002/adhm.202100223
DO - 10.1002/adhm.202100223
M3 - Article
C2 - 33890430
AN - SCOPUS:85104618928
SN - 2192-2640
VL - 10
JO - Advanced Healthcare Materials
JF - Advanced Healthcare Materials
IS - 12
M1 - 2100223
ER -