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Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury
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Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury
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Journal Article
Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury
2012
Overview
Organ fibrosis often leads to end-stage organ failure, but the origin of key profibrotic cell types is still unclear. Lucie Peduto and her colleagues have used genetic lineage tracing and pharmacological ablation techniques to show that ADAM12
+
perivascular cells are a key source of profibrotic cells in acute skin and muscle injury in the mouse. They also show that knockdown of ADAM12 expression is beneficial, suggesting a possible therapeutic target for the treatment of fibrosis.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Biomedical and Life Sciences
/ Cicatrix
/ Cobra Cardiotoxin Proteins - toxicity
/ Collagen
/ Dermis
/ Fibrosis
/ Freund's Adjuvant - toxicity
/ Growth
/ Injuries
/ Mice
/ Muscle, Skeletal - metabolism
/ Muscle, Skeletal - pathology
/ Proteins
/ Receptor, Platelet-Derived Growth Factor alpha
/ Receptor, Platelet-Derived Growth Factor alpha - analysis
/ Specific Pathogen-Free Organisms
/ Tissues
