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J. Biol. Chem., Vol. 282, Issue 31, 22910-22920, August 3, 2007

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Differentiation of Human Circulating Fibrocytes as Mediated by Transforming Growth Factor- and Peroxisome Proliferator-activated Receptor ^*

Kurt M. Hong, John A. Belperio^¶, Michael P. Keane^¶, Marie D. Burdick^||, and Robert M. Strieter^||1

From the Center for Human Nutrition and the Departments of Pathology and Laboratory Medicine and ^¶Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California 90024 and the ^||Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Fibrocytes are a distinct population of fibroblast-like progenitor cells in peripheral blood that have recently been shown to possess plasticity to differentiate along mesenchymal lineages, including commitment to myofibroblast and adipocyte cells. Here, we demonstrated that transforming growth factor (TGF) 1 drives fibrocyte-to-myofibroblast differentiation through activating Smad2/3 and SAPK/JNK MAPK pathways, which in turn stimulates -smooth muscle actin expression. We determined that SAPK/JNK signaling acts in a positive feedback loop to modulate Smad2/3 nuclear availability and Smad2/3-dependent transcription. Conversely, fibrocyte-to-adipocyte differentiation is driven by the peroxisome proliferator-activated receptor (PPAR) agonist troglitazone, which is associated with cytoplasmic lipid accumulation and induction of aP2. Treatment with troglitazone also disrupted TGF1-activated SAPK/JNK signaling, leading to decreased Smad2/3 transactivation activity and -smooth muscle actin expression. Interestingly, TGF1 was demonstrated to have reciprocal inhibition on fibrocyte differentiation to adipocytes. By activating SAPK/JNK signaling, which is normally suppressed during adipogenesis, PPAR-dependent transactivation activity and induction of aP2 expression were disrupted. Taken together, within the context of the local microenvironmental niche, the delicate balance of PPAR and TGF1 activation drives the selection of an adipocyte or myofibroblast differentiation pathway through SAPK/JNK signaling.

Received for publication, May 1, 2007

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Hospital Dr., P. O. Box 800466, Charlottesville, VA 22908. Fax: 434-243-0399; E-mail: strieter{at}virginia.edu.

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