IL-4 induces differentiation of human embryonic stem cells into fibrogenic fibroblast-like cells

Tadashi Sato, Xiangde Liu, Hesham Basma, Shinsaku Togo, Hisatoshi Sugiura, Amy Nelson, Masanori Nakanishi, Nobuhiro Kanaji, Xingqi Wang, Miok Kim, Yingji Li, Joel Michalski, Maha Farid, John G. Sharp, Stephen I. Rennard

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Background: Fibroblast heterogeneity is recognized, and fibroblasts from diseased tissues, including those of asthmatic subjects, have functional phenotypes that differ from normal tissue. However, progenitor-progeny relationships and the factors that control fibroblast differentiation are poorly defined. Objective: We sought to determine whether IL-4 could alter the functional phenotype of fibroblasts during their differentiation from stem/progenitor cells. Methods: Using a 3-dimensional collagen gel system, we obtained embryoid bodies derived from human embryonic stem cells and recovered spindle-shaped cells consistent with fibroblasts that had differentiated in the presence or absence of IL-4. Results: IL-4-induced fibroblast-like cells were more active in contraction of collagen gels, migration, and production of fibronectin than control (without IL-4) cells. IL-4-induced cells demonstrated less expression of miR-155, which modulated contraction, migration, and fibronectin production. These differences persisted in culture without further addition of IL-4, suggesting the differentiated phenotype might be a permanent alteration. Conclusion: The current study demonstrates that IL-4 induces differentiation of stem/precursor cells into fibroblast-like cells that demonstrate a more fibrogenic phenotype, which is due to reduced expression of miR-155. These findings provide a novel mechanism for the persistent abnormalities in IL-4-related diseases and a novel target to regulate tissue remodeling by fibroblasts.

Original languageEnglish (US)
Pages (from-to)1595-1603.e9
JournalJournal of Allergy and Clinical Immunology
Volume127
Issue number6
DOIs
StatePublished - Jun 2011

Keywords

  • Embryonic stem cells, fibroblasts, IL-4, fibrosis, asthma, microRNA
  • miR-155, chemotaxis, collagen gel contraction, TGF-β

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Sato, T., Liu, X., Basma, H., Togo, S., Sugiura, H., Nelson, A., Nakanishi, M., Kanaji, N., Wang, X., Kim, M., Li, Y., Michalski, J., Farid, M., Sharp, J. G., & Rennard, S. I. (2011). IL-4 induces differentiation of human embryonic stem cells into fibrogenic fibroblast-like cells. Journal of Allergy and Clinical Immunology, 127(6), 1595-1603.e9. https://doi.org/10.1016/j.jaci.2011.01.049