Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling
The progenitor cells of the developing liver can differentiate toward both hepatocyte and biliary cell fates. In addition to the established roles of TGFβ and Notch signaling in this fate specification process, there is increasing evidence that liver progenitors are sensitive to mechanical cues. Here, we utilized microarrayed patterns to provide a controlled biochemical and biomechanical microenvironment for mouse liver progenitor cell differentiation. In these defined circular geometries, we observed biliary differentiation at the periphery and hepatocytic differentiation in the center. Parallel measurements obtained by traction force microscopy showed substantial stresses at the periphery, coincident with maximal biliary differentiation. We investigated the impact of downstream signaling, showing that peripheral biliary differentiation is dependent not only on Notch and TGFβ but also E-cadherin, myosin-mediated cell contractility, and ERK. We have therefore identified distinct combinations of microenvironmental cues which guide fate specification of mouse liver progenitors toward both hepatocyte and biliary fates.
Source data tables (9 total) for the immunofluorescence and TFM array experiments have been attached to this submission and are associated with the relevant figures. Source code files (11 total) have been uploaded for the TFM analysis (Figure 4-6), FEM simulations (Figure 4), and Notch simulations (Figure 5). A detailed protocol for our array analysis technique together with source code has been made available elsewhere, see Kaylan et al. (J Vis Exp, 2017, e55362, http://dx.doi.org/10.3791/55362).
Article and author information
National Institute of Biomedical Imaging and Bioengineering (5R03EB022254-02)
- Gregory H Underhill
National Science Foundation (1636175)
- Gregory H Underhill
National Institute of Biomedical Imaging and Bioengineering (T32EB019944)
- Ian C Berg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- Gordana Vunjak-Novakovic, Columbia University, United States
- Received: May 21, 2018
- Accepted: December 24, 2018
- Accepted Manuscript published: December 27, 2018 (version 1)
- Version of Record published: January 22, 2019 (version 2)
© 2018, Kaylan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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