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Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses

Fibrosis is one of the hallmarks of chronic liver disease and is associated with aberrant wound healing. Changes in the composition of the liver microenvironment during fibrosis result in a complex crosstalk of extracellular cues that promote altered behaviors in the cell types that comprise the liv...

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Autores principales: Brougham-Cook, Aidan, Kimmel, Hannah R. C., Monckton, Chase P., Owen, Daniel, Khetani, Salman R., Underhill, Gregory H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AIP Publishing LLC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9637025/
https://www.ncbi.nlm.nih.gov/pubmed/36345318
http://dx.doi.org/10.1063/5.0097602
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author Brougham-Cook, Aidan
Kimmel, Hannah R. C.
Monckton, Chase P.
Owen, Daniel
Khetani, Salman R.
Underhill, Gregory H.
author_facet Brougham-Cook, Aidan
Kimmel, Hannah R. C.
Monckton, Chase P.
Owen, Daniel
Khetani, Salman R.
Underhill, Gregory H.
author_sort Brougham-Cook, Aidan
collection PubMed
description Fibrosis is one of the hallmarks of chronic liver disease and is associated with aberrant wound healing. Changes in the composition of the liver microenvironment during fibrosis result in a complex crosstalk of extracellular cues that promote altered behaviors in the cell types that comprise the liver sinusoid, particularly liver sinusoidal endothelial cells (LSECs). Recently, it has been observed that LSECs may sustain injury before other fibrogenesis-associated cells of the sinusoid, implicating LSECs as key actors in the fibrotic cascade. A high-throughput cellular microarray platform was used to deconstruct the collective influences of defined combinations of extracellular matrix (ECM) proteins, substrate stiffness, and soluble factors on primary human LSEC phenotype in vitro. We observed remarkable heterogeneity in LSEC phenotype as a function of stiffness, ECM, and soluble factor context. LYVE-1 and CD-31 expressions were highest on 1 kPa substrates, and the VE-cadherin junction localization was highest on 25 kPa substrates. Also, LSECs formed distinct spatial patterns of LYVE-1 expression, with LYVE-1+ cells observed in the center of multicellular domains, and pattern size regulated by microenvironmental context. ECM composition also influenced a substantial dynamic range of expression levels for all markers, and the collagen type IV was observed to promote elevated expressions of LYVE-1, VE-cadherin, and CD-31. These studies highlight key microenvironmental regulators of LSEC phenotype and reveal unique spatial patterning of the sinusoidal marker LYVE-1. Furthermore, these data provide insight into understanding more precisely how LSECs respond to fibrotic microenvironments, which will aid drug development and identification of targets to treat liver fibrosis.
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spelling pubmed-96370252022-11-06 Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses Brougham-Cook, Aidan Kimmel, Hannah R. C. Monckton, Chase P. Owen, Daniel Khetani, Salman R. Underhill, Gregory H. APL Bioeng Articles Fibrosis is one of the hallmarks of chronic liver disease and is associated with aberrant wound healing. Changes in the composition of the liver microenvironment during fibrosis result in a complex crosstalk of extracellular cues that promote altered behaviors in the cell types that comprise the liver sinusoid, particularly liver sinusoidal endothelial cells (LSECs). Recently, it has been observed that LSECs may sustain injury before other fibrogenesis-associated cells of the sinusoid, implicating LSECs as key actors in the fibrotic cascade. A high-throughput cellular microarray platform was used to deconstruct the collective influences of defined combinations of extracellular matrix (ECM) proteins, substrate stiffness, and soluble factors on primary human LSEC phenotype in vitro. We observed remarkable heterogeneity in LSEC phenotype as a function of stiffness, ECM, and soluble factor context. LYVE-1 and CD-31 expressions were highest on 1 kPa substrates, and the VE-cadherin junction localization was highest on 25 kPa substrates. Also, LSECs formed distinct spatial patterns of LYVE-1 expression, with LYVE-1+ cells observed in the center of multicellular domains, and pattern size regulated by microenvironmental context. ECM composition also influenced a substantial dynamic range of expression levels for all markers, and the collagen type IV was observed to promote elevated expressions of LYVE-1, VE-cadherin, and CD-31. These studies highlight key microenvironmental regulators of LSEC phenotype and reveal unique spatial patterning of the sinusoidal marker LYVE-1. Furthermore, these data provide insight into understanding more precisely how LSECs respond to fibrotic microenvironments, which will aid drug development and identification of targets to treat liver fibrosis. AIP Publishing LLC 2022-11-04 /pmc/articles/PMC9637025/ /pubmed/36345318 http://dx.doi.org/10.1063/5.0097602 Text en © 2022 Author(s). https://creativecommons.org/licenses/by/4.0/All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Articles
Brougham-Cook, Aidan
Kimmel, Hannah R. C.
Monckton, Chase P.
Owen, Daniel
Khetani, Salman R.
Underhill, Gregory H.
Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses
title Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses
title_full Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses
title_fullStr Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses
title_full_unstemmed Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses
title_short Engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses
title_sort engineered matrix microenvironments reveal the heterogeneity of liver sinusoidal endothelial cell phenotypic responses
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9637025/
https://www.ncbi.nlm.nih.gov/pubmed/36345318
http://dx.doi.org/10.1063/5.0097602
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