Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury

Abstract

Profibrotic cells that develop upon injury generate permanent scar tissue and impair organ recovery, though their origin and fate are unclear. Here we show that transient expression of ADAM12 (a disintegrin and metalloprotease 12) identifies a distinct proinflammatory subset of platelet-derived growth factor receptor-α-positive stromal cells that are activated upon acute injury in the muscle and dermis. By inducible genetic fate mapping, we demonstrate in vivo that injury-induced ADAM12(+) cells are specific progenitors of a major fraction of collagen-overproducing cells generated during scarring, which are progressively eliminated during healing. Genetic ablation of ADAM12(+) cells, or knockdown of ADAM12, is sufficient to limit generation of profibrotic cells and interstitial collagen accumulation. ADAM12(+) cells induced upon injury are developmentally distinct from muscle and skin lineage cells and are derived from fetal ADAM12(+) cells programmed during vascular wall development. Thus, our data identify injury-activated profibrotic progenitors residing in the perivascular space that can be targeted through ADAM12 to limit tissue scarring.

Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction

“…Because it is difficult to acquire a sufficient number of resident cardiac fibroblasts from mice for in vitro experiments, we used a transdifferentiation system using rat neonatal resident cardiac fibroblasts (41). As reported previously (41), treatment of rat neonatal resident cardiac fibroblasts with TGF-β1 induced the expression of Acta2, which encodes αSMA, and a disintegrin and metalloproteinase 12 (ADAM12), another myofibroblast marker protein (43) (Figure 8A), indicating that the resident fibroblasts were transdifferentiated. In the TGF-β1-stimulated resident fibroblasts, Mfge8 expression was induced ( Figure 8A) with a time course similar to those of Acta2 and Adam12 ( Figure 8A).…”

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis

“…At present, pericytes are considered one of the most important players in different fibrotic diseases 4,40,41 . Dulauroy, et al 19 , using genetic studies in mice to observe neural crest cell-derived embryonic mesenchyme, which expresses the ADAM12, found that fetal ADAM12+ cells contribute to the generation of perivascular cells in adult skeletal muscle. In fact, a subset of these cells deriving from the ADAM12+ lineage expressed pericytes markers and wrapped-around capillaries.…”

“…In fact, lineage tracing experiments, in an experimental model of kidney fibrosis 19 , confirmed that these cells are the main source of myofibroblasts, and the perivascular progenitor cells, with a profibrotic function, may be identified by the expression of 1 specific marker, the isoform 12 of ADAM (ADAM12) 20 . It is well known that the main expression of ADAM12 may be observed during embryonic morphogenesis of skeletal muscles and visceral organs, and intriguingly this molecule may be newly expressed in several human fibrotic diseases 21,22,23,24,25,26 .…”

Fibroblast heterogeneity: implications for human disease

“…Within muscle, it appears that pericytes have the capability to differentiate to muscle fibers (37), but at the present time there is no evidence that pericytes have the capability to differentiate into other dermal lineages. A specific subset of ADAM12-expressing perivascular fibroblasts present in skin and muscle are activated by wounding and contribute to collagen overproduction in the scar (38). Genetic ablation of these cells reduces collagen production and scarring (38).…”