Abstract
The primary cilium is an organelle, present at the cell surface, with various biological functions. We, and others, have shown that it plays a role in the differentiation of adipose progenitors (APs) into adipocytes. APs can also differentiate into myofibroblasts when treated with TGF-β1. Several components of the TGF-β1 pathway are located within the cilium suggesting a function for this organelle in AP myofibrogenesis. We studied differentiation of APs into myofibroblasts in two human models: APs of the adipose tissue (aAPs) and APs resident in the skeletal muscles (mAPs). We showed that, in vivo, myofibroblasts within muscles of patients with Duchenne Muscular Dystrophy were ciliated. In vitro, myofibroblasts derived from APs maintained a functional primary cilium. Using HPI4, a small molecule that inhibits ciliogenesis, and siRNA against Kif-3A, we provide evidence that the primary cilium is necessary both for the differentiation of APs into myofibroblasts and the maintenance of the phenotype. Disruption of the primary cilium inhibited TGF-β1-signalisation providing a molecular mechanism by which the cilium controls myofibroblast differentiation. These data suggest that myofibroblasts from various origins are controlled differently by their primary cilium.
Highlights
Myofibroblasts appear after tissue lesion and play an active role in tissue repair[1,2]
We studied the response of the cells to Sonic Hedgehog (Shh) which signaling pathway depends upon the cilium. APs of the adipose tissue (aAPs) were treated with or without TGF-β1 for 3 days to convert them into myofibroblasts
We studied if the effect of HPI-4 was specific to cilia-associated signaling. aAPs were treated for various times with TGF-β1, EGF or fetal calf serum (FCS) in cells pre-treated or not with HPI-4 (Fig. 6b)
Summary
Myofibroblasts appear after tissue lesion and play an active role in tissue repair[1,2]. In most cases associated with inflammation, myofibroblasts persist This results in an excess of extracellular matrix deposition that can modify the structure of the tissue and affects the homeostasis of the organ, a process called fibrosis[3,4]. We have investigated if the cilium was involved in the differentiation of mesenchymal human aAPs and mAPs into myofibroblasts after TGF-β1 treatment. Loss of the cilium was associated with a decrease in TGF-β1 induced Smad phosphorylation. Together, these data pointed to a crucial function of the primary cilium in the differentiation of APs into myofibroblasts and suggest that myofibroblasts from different origins behave differently
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