The perivascular origin of pathological fibroblasts

Abstract

The ability to repair tissues is essential for the survival of organisms. In chronic settings, the failure of the repair process to terminate results in overproduction of collagen, a pathology known as fibrosis, which compromises organ recovery and impairs function. The origin of the collagen-overproducing cell has been debated for years. Here we review recent insights gained from the use of lineage tracing approaches in several organs. The resulting evidence points toward specific subsets of tissue-resident mesenchymal cells, mainly localized in a perivascular position, as the major source for collagen-producing cells after injury. We discuss these findings in view of the functional heterogeneity of mesenchymal cells of the perivascular niche, which have essential vascular, immune, and regenerative functions that need to be preserved for efficient repair.

Origin and functional heterogeneity of fibroblasts

“…Other types of transition programs contribute to the fibroblast pool in tissue fibrosis and tumors, including EndMT, pericyte and adipocyte‐to‐fibroblast transitions . With respect to the perivascular source of fibroblasts, it should also be noted that large blood vessels contain perivascular fibroblasts (Table ) along the outermost layer (vascular adventitia), and are also referred to as adventitial fibroblasts .…”

“…41 The perivascular origin of fibroblasts needs more work to define their heterogeneity and functional contribution to disease, including their possible role as vascular progenitor cells. 41,90 The functional outcome of these distinct niches of fibroblasts is under active study, and insights from such effort will likely refine the definition of FAFs, CAFs, and AAFs ( Table 2).…”

Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair

“…Liver pericytes positive for CD146, but negative for the classical HSC markers αSMA and glial fibrillary acidic protein (GFAP), have been described too [44], and pericytes without specific HSC characteristics exist in the portal vessels and central vein [45]. Likewise, perivascular cells in the liver do not comprise only pericytes, as other mesenchymal cells including fibroblasts and smooth muscle cells can be found around larger blood vessels [46]. KCs, in turn, are associated with endothelial cells in the lumen of sinusoids to play their role as a liver-specific type of macrophage [47].…”

Inhibition of COX‐2 Pathway as a Potential Prophylaxis Against Arthrofibrogenesis in a Rabbit Model of Joint Contracture

“…Activation of the arthrofibrotic process is thought to occur secondary to enhanced myofibroblast expression of α‐smooth muscle actin (α‐SMA) which contributes to increased collagen production and abnormally stiffened ECM surrounding the joint capsule . Failure to terminate myofibroblast activation has been correlated with continued host immune system response following injury . Numerous cell types including macrophages, neutrophils, and mast cells have also been shown to secrete cytokines (specifically TGF‐β) and chemokines involved in prolonged fibroblast activation .…”

“…Numerous cell types including macrophages, neutrophils, and mast cells have also been shown to secrete cytokines (specifically TGF‐β) and chemokines involved in prolonged fibroblast activation . Although the increased presence of inflammatory cell products correlates with disease severity in various organ systems, its behavior in synovial tissue remains to be addressed . Recent evidence suggests that the cellular transition from fibroblast to myofibroblast following injury may, in and of itself, promote further inflammation in the surrounding tissue .…”