Investigating the role of the extracellular environment in modulating hepatic stellate cell biology with arrayed combinatorial microenvironments

David Brafman, Samuele De Minicis, Ekihiro Seki, Kevan D. Shah, Dayu Teng, David Brenner, Karl Willert, Shu Chien

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Hepatic stellate cells (HSCs) are a major cell type of the liver that are involved in liver homeostasis. Upon liver damage, HSCs exit their normally quiescent state and become activated, leading to an increase of their proliferation, production of abnormal extracellular matrix proteins (ECMPs) and inflammatory mediators, and eventually liver fibrosis and cirrhosis. Current in vitro approaches to identify components that influence HSC biology typically investigate one factor at a time and generally ignore the complex crosstalk among the myriad of components that comprise the microenvironments of quiescent or activated HSCs. Here we describe a high throughput screening (HTS) approach to identify factors that affect HSC biology. Specifically, we integrated the use of ECMPs and signaling molecules into a combinatorial cellular microarray technology platform, thereby creating comprehensive " microenvironments". Using this technology, we performed real-time simultaneous screening of the effects of hundreds of unique microenvironments composed of ECMPs and signaling molecules on HSC proliferation and activation. From these screens, we identified combinations of microenvironment components that differentially modulate the HSC phenotype. Furthermore, analysis of HSC responses revealed that the influences of Wnt signaling molecules on HSC fate are dependent on the ECMP composition in which they are presented. Collectively, our results demonstrate the utility of high-content, array-based screens to provide a better understanding of HSC biology. Our results indicate that array-based screens may provide an efficient means for identifying candidate signaling pathways to be targeted for anti-fibrotic therapies.

Original languageEnglish (US)
Pages (from-to)513-524
Number of pages12
JournalIntegrative Biology
Volume1
Issue number8-9
DOIs
StatePublished - 2009
Externally publishedYes

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Cytology
Hepatic Stellate Cells
Cell Biology
Extracellular Matrix Proteins
Liver
Liver Cirrhosis
Molecules
Screening
Technology
Cell proliferation
Microarrays
Crosstalk
Homeostasis
Chemical activation
Cell Proliferation
Throughput

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Medicine(all)

Cite this

Investigating the role of the extracellular environment in modulating hepatic stellate cell biology with arrayed combinatorial microenvironments. / Brafman, David; De Minicis, Samuele; Seki, Ekihiro; Shah, Kevan D.; Teng, Dayu; Brenner, David; Willert, Karl; Chien, Shu.

In: Integrative Biology, Vol. 1, No. 8-9, 2009, p. 513-524.

Research output: Contribution to journalArticle

Brafman, David ; De Minicis, Samuele ; Seki, Ekihiro ; Shah, Kevan D. ; Teng, Dayu ; Brenner, David ; Willert, Karl ; Chien, Shu. / Investigating the role of the extracellular environment in modulating hepatic stellate cell biology with arrayed combinatorial microenvironments. In: Integrative Biology. 2009 ; Vol. 1, No. 8-9. pp. 513-524.
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