Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma.
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) beta1 drives fibrocyte-to-myofibroblast differentiation through activating Smad2/3 and SAPK/JNK MAPK pathways, which in turn stimulates alpha-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) gamma agonist troglitazone, which is associated with cytoplasmic lipid accumulation and induction of aP2. Treatment with troglitazone also disrupted TGF beta 1-activated SAPK/JNK signaling, leading to decreased Smad2/3 transactivation activity and alpha-smooth muscle actin expression. Interestingly, TGF beta 1 was demonstrated to have reciprocal inhibition on fibrocyte differentiation to adipocytes. By activating SAPK/JNK signaling, which is normally suppressed during adipogenesis, PPARgamma-dependent transactivation activity and induction of aP2 expression were disrupted. Taken together, within the context of the local microenvironmental niche, the delicate balance of PPARgamma and TGF beta 1 activation drives the selection of an adipocyte or myofibroblast differentiation pathway through SAPK/JNK signaling.
Hong
Kurt M
KM
Center for Human Nutrition and the Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California 90024, USA.
Belperio
John A
JA
Keane
Michael P
MP
Burdick
Marie D
MD
Strieter
Robert M
RM
D000199:Actins / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D002454:Cell Differentiation; D002839:Chromans / Q000494:pharmacology; D003239:Connective Tissue Cells / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D047495:PPAR gamma / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000077288:Troglitazone
D000199:Actins; D002839:Chromans; D004791:Enzyme Inhibitors; D047495:PPAR gamma; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D048670:MAP Kinase Kinase 4; D000077288:Troglitazone