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

Abstract

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 TGF␤1-activated SAPK/JNK signaling, leading to decreased Smad2/3 transactivation activity and ␣-smooth muscle actin expression. Interestingly, TGF␤1 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 TGF␤1 activation drives the selection of an adipocyte or myofibroblast differentiation pathway through SAPK/ JNK signaling.

The Synthetic Peroxisome Proliferator-Activated Receptor-γ Agonist Ciglitazone Attenuates Neuroinflammation and Accelerates Encapsulation in Bacterial Brain Abscesses

“…This finding was revealed by enhanced fibronectin deposition and the earlier appearance of myofibroblasts expressing ␣-smooth muscle actin. This finding is at direct odds with other literature demonstrating that PPAR-␥ agonists attenuate myofibroblast differentiation or fibrosis in models of pathological fibrosis such as scleroderma or pulmonary/hepatic fibrosis (52)(53)(54)(55)(56). However, it is important to acknowledge a fundamental difference between these models of excessive fibrosis vs brain abscess in which a highly regulated fibrotic wall forms in a region-specific manner.…”

“…In contrast, in models of fibrosis, the actions of PPAR-␥ ligands have, in large part, been shown to be receptordependent (52)(53)(54). Therefore, it is highly likely that ciglitazone may exert both receptor-dependent and -independent effects in brain abscesses through its ability to accelerate fibrosis and inhibit inflammatory responses, respectively.…”

What Differentiates Normal Lung Repair and Fibrosis?: Inflammation, Resolution of Repair, and Fibrosis

“…Because fibrocytes are a distinct population of fibroblast-like progenitor cells in the peripheral blood that have been shown to possess plasticity to differentiate along mesenchymal lineages (e.g., commitment to become myofibroblasts and adipocytes), Hong and colleagues were able to demonstrate the signaling pathways that are necessary to drive fibrocytes to myofibroblast or adipocyte differentiation (40). Myofibroblast differentiation was mediated in the presence of TGF-b activation through activating Smad2/3 and stress-activated protein kinase/c-Jun Nterminal kinase (SAPK/JNK) mitogen-activated protein kinase (MAPK) pathways, which in turn induced a-SMA expression (40).…”

“…Myofibroblast differentiation was mediated in the presence of TGF-b activation through activating Smad2/3 and stress-activated protein kinase/c-Jun Nterminal kinase (SAPK/JNK) mitogen-activated protein kinase (MAPK) pathways, which in turn induced a-SMA expression (40). They determined that SAPK/JNK signaling acts in a positive feedback loop to modulate Smad2/3 nuclear availability and Smad2/3-dependent transcription (40).…”

Fibrocytes are involved in the pathogenesis of human chronic kidney disease

“…Especially, p38MAPK is phosphorylated in response to hyperosmolarity, oxidative stress, and inflammatory cytokines, thereby contributing to the activation of nuclear transcription factors, including nuclear factor (NF)-κB, which principally regulates the gene expression of various chemokines, such as CCL2 [31]. In addition, the expression of type I collagen is also regulated by the MAPK family in cultured fibrocytes [32]. Taken The clinical management of CKD remains to be investigated due to a lack of effective treatment or accurate indicators of disease progression.…”