Chronic tissue inflammation is associated with the presence of specific connective-tissue cells, known as myofibroblasts. These lead to the formation of fibrosis. Researchers from Inserm have identified a mechanism crucial to the formation of these cells from human adipocyte stem cells in adipose and muscle tissue. The primary cilium, at the origin of the differentiation pathway, could constitute a therapeutic target in the fight against the fibrosis encountered in obesity and certain muscle diseases such as Duchenne Muscular Dystrophy.
Myofibroblasts are cells involved in tissue repair. They are particularly active at lesion sites where they secrete collagen to promote healing. In addition, they possess contractile proteins that pull wound edges together. Normally, these cells disappear once the wound has healed. But in certain pathological conditions – such as chronic inflammation – they remain activated, leading to the formation of fibrosis.
This phenomenon is not confined to the skin, it also occurs in numerous other organs. As such, the moderate chronic inflammation observed in individuals with obesity can trigger fibrosis in the adipose tissue, which itself can lead to the development of insulin dependence. In Duchenne Muscular Dystrophy, chronic inflammation of the muscle tissue triggers myofibroblast invasion and degeneration of the muscle, in which its mechanical capacities are progressively reduced. Such fibrotic processes can also affect the liver, heart and lungs.
The origin of the myofibroblasts responsible for this fibrosis depends on the tissues concerned. They are derived from fibroblasts in the skin, from epithelial cells in the kidneys and lungs, mesenchymal cells in the heart, and adipocyte stem cells in the adipose and muscle tissues. The processes leading to these various differentiation pathways vary and little is known about them at present.
When a poorly known cell component plays a starring role
"We’ve been researching adipocyte stem cells for a long time," explains Pascal Peraldi* co-author of the paper published recently in Scientific Reports on myofibroblast differentiation. "In previous research we showed that the primary cilium is involved in the differentiation of these stem cells into adipocytes. In addition, other teams have identified receptors for growth factor TGF-b1 on the primary cilium, which is relevant because TGF-b1 is the principal molecule that induces myofibroblast differentiation. So we wanted to know whether this TGF-b1 pathway is involved in the differentiation of these adipocyte stem cells into myofibroblasts and whether or not it is dependent on the primary cilium."
The primary cilium is an organelle that resembles a single flagellum, a sort of antenna, which exists in almost all cell types. It enables the cell to capture mechanical signals, such as urine flow in the kidneys, as well as biochemical signals in the form of molecular messengers circulating in its environment. Once these messengers are bound to their receptors that are present on the cilium, they activate the corresponding intracellular signaling pathways.
As yet poorly known, interest in the primary cilium is growing, particularly regarding its involvement in the processes of cell differentiation and proliferation.
Peraldi and his colleagues have conducted in vitro research into the role of this cilium in the differentiation of human adipocyte stem cells into myofibroblasts. Research which has revealed the cilium is essential to the differentiation process induced by the presence of TFG-b1. It has also revealed that the cilium is necessary in maintaining the myofibroblasts in a functional state, i.e. able to secrete collagen and contractile proteins. Indeed, when the cilium is destroyed (by adding HPI-4), this activity stops.
"So the process we revealed is different from what might be observed in the kidney, for example," emphasizes Peraldi. "In this organ, the differentiation into myofibroblasts is accompanied by a loss of the cilium. This research thus confirms the diversity of the differentiation pathways, at the same time as their more or less marked dependence on the primary cilium."
This research also provides a better understanding of the mechanisms at work, making it feasible to envisage manipulating the cilium to modulate the signaling pathways. As such, finding a molecule able to – very specifically – destroy the primary cilium in adipose or muscle tissue could confer a useful antifibrotic effect. "But we must proceed with caution: in non-fibrotic areas, it’s essential to maintain the integrity of the primary cilium! Diseases related to a dysfunction of this organelle, known as ciliopathies, are evidence of this."
* Unit 1091 Inserm/CNRS/Université Nice Sophia Antipolis, Stem cells and differentiation team, Institute of Biology Valrose, Nice.
N. Arrighi et al. The primary cilium is necessary for the differentiation and the maintenance of human adipose progenitors into myofibroblasts. Scientific Reports 7, Article number: 15248 (2017) doi:10.1038/s41598-017-15649-2