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

• Published in: Journal of allergy and clinical immunology Vol. 127; no. 6; pp. 1595 - 1603.e9
• Main Authors: Sato, Tadashi, MD, PhD, Liu, Xiangde, MD, Basma, Hesham, PhD, Togo, Shinsaku, MD, PhD, Sugiura, Hisatoshi, MD, PhD, Nelson, Amy, BS, Nakanishi, Masanori, MD, PhD, Kanaji, Nobuhiro, MD, PhD, Wang, Xingqi, MD, Kim, Miok, MD, Li, Yingji, MD, PhD, Michalski, Joel, BS, Farid, Maha, MD, Sharp, John G., PhD, Rennard, Stephen I., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01-06-2011; Elsevier; Elsevier Limited
• Subjects: Actins - metabolism; Allergy and Immunology; Antibiotics; Biological and medical sciences; Cell Culture Techniques; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Lineage; Chronic obstructive pulmonary disease, asthma; Collagen; Cytokines; Digital cameras; Embryoid Bodies - cytology; Embryoid Bodies - drug effects; Embryoid Bodies - metabolism; Embryonic Stem Cells - cytology; Embryonic Stem Cells - drug effects; Embryonic Stem Cells - metabolism; Embryonic stem cells, fibroblasts, IL-4, fibrosis, asthma, microRNA; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gels; Humans; Immunopathology; Interleukin-4 - pharmacology; Laboratories; Medical sciences; MicroRNAs; MicroRNAs - genetics; miR-155, chemotaxis, collagen gel contraction, TGF-β; Phenotype; Pneumology; Proteins; Recombinant Proteins - pharmacology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Stem cells; Embryonic stem cells, fibroblasts, IL-4, fibrosis, asthma, microRNA; Prostaglandin; Basic fibroblast growth factor; Embryoid body; bFGF; α-SMA; DMEM; Human embryonic stem cell; miR-155, chemotaxis, collagen gel contraction, TGF-β; FITC; α Smooth muscle actin; MicroRNA; Dulbecco modified Eagle medium; Fluorescein isothiocyanate stain–green immunofluorescence; PG; miRNA; EB; hESC; RNA interference; Transforming growth factor β; Stem cell; Interleukin 4; fibroblasts; Immunology; collagen gel contraction; Bronchus disease; TGF-β; Obstructive pulmonary disease; Human; Lung disease; Immunopathology; Respiratory disease; Cytokine; Glycoprotein; Micro RNA; IL-4; Cell differentiation; Embryonic stem cells; Chemotaxis; Asthma; Gene silencing; Embryonic cell; Collagen; miR-155; Fibrosis; microRNA; Differentiation; Fibroblast
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2011.01.049

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.