Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling

Kerim B. Kaylan; Ian C. Berg; Matthew J. Biehl; Aidan Brougham-Cook; Ishita Jain; Sameed M. Jamil; Lauren H. Sargeant; Nicholas J. Cornell; Lori T. Raetzman; Gregory H. Underhill

doi:10.7554/eLife.38536

Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling

Kerim B. Kaylan, Ian C. Berg, Matthew J. Biehl, Aidan Brougham-Cook, Ishita Jain, Sameed M. Jamil, Lauren H. Sargeant, Nicholas J. Cornell, Lori T. Raetzman, Gregory H. Underhill

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Abstract

The progenitor cells of the developing liver can differentiate toward both hepatocyte and biliary cell fates. In addition to the established roles of TGFb 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 TGFb 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.

Original language	English (US)
Article number	e38536
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.38536
State	Published - Dec 1 2018

ASJC Scopus subject areas

Neuroscience(all)
Immunology and Microbiology(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.7554/eLife.38536

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title = "Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling",

abstract = "The progenitor cells of the developing liver can differentiate toward both hepatocyte and biliary cell fates. In addition to the established roles of TGFb 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 TGFb 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.",

author = "Kaylan, {Kerim B.} and Berg, {Ian C.} and Biehl, {Matthew J.} and Aidan Brougham-Cook and Ishita Jain and Jamil, {Sameed M.} and Sargeant, {Lauren H.} and Cornell, {Nicholas J.} and Raetzman, {Lori T.} and Underhill, {Gregory H.}",

note = "Funding Information: The authors gratefully acknowledge H{\`e}l{\'e}ne Strick-Marchand and Mary C Weiss (Institut Pasteur) for providing BMEL cells. We would also like to thank Dianwen Zhang (Imaging Technology Group, Beckman Institute) for assistance with microarray imaging and Karen Weis (Molecular Physiology, University of Illinois at Urbana–Champaign) for advice and materials. 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. Publisher Copyright: {\textcopyright} Kaylan et al.",

year = "2018",

month = dec,

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doi = "10.7554/eLife.38536",

language = "English (US)",

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T1 - Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling

AU - Kaylan, Kerim B.

AU - Berg, Ian C.

AU - Biehl, Matthew J.

AU - Brougham-Cook, Aidan

AU - Jain, Ishita

AU - Jamil, Sameed M.

AU - Sargeant, Lauren H.

AU - Cornell, Nicholas J.

AU - Raetzman, Lori T.

AU - Underhill, Gregory H.

N1 - Funding Information: The authors gratefully acknowledge Hèléne Strick-Marchand and Mary C Weiss (Institut Pasteur) for providing BMEL cells. We would also like to thank Dianwen Zhang (Imaging Technology Group, Beckman Institute) for assistance with microarray imaging and Karen Weis (Molecular Physiology, University of Illinois at Urbana–Champaign) for advice and materials. 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. Publisher Copyright: © Kaylan et al.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The progenitor cells of the developing liver can differentiate toward both hepatocyte and biliary cell fates. In addition to the established roles of TGFb 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 TGFb 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.

AB - The progenitor cells of the developing liver can differentiate toward both hepatocyte and biliary cell fates. In addition to the established roles of TGFb 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 TGFb 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.

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Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling

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