Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis

Abstract

Summary Idiopathic pulmonary fibrosis (IPF) is a form of progressive interstitial lung disease with unknown etiology. Due to a lack of effective treatment, IPF is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function and hindering gas exchange. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution. Genetic engineering in mice enables the time-controlled labeling and monitoring of lipogenic or myogenic populations of lung fibroblasts during fibrosis formation and resolution. Our data demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during fibrosis formation. Conversely, we observed a myogenic-to-lipogenic switch during fibrosis resolution. Analysis of human lung tissues and primary human lung fibroblasts indicates that this fate switching is involved in IPF pathogenesis, opening potential therapeutic avenues to treat patients.

Origin and characterization of alpha smooth muscle actin-positive cells during murine lung development

“…N, O). This line also allows labeling the absolute majority of SMCs in the adult lung . One of the questions that we tried to answer was whether pre‐existing ACTA2 + cells at early lung development serve as progenitors for future SMCs that progressively appear as the epithelial tubes undergo iterative branching.…”

Scars or Regeneration?—Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

“…Here, fibroblasts appear to display a phenotypic plasticity towards lipogenic and myogenic lung fibroblasts. A transition towards a myogenic contractile lung fibroblast determines fibrosis formation, whereas a transition towards lipogenic cells is seen during resolution of fibrosis, and this phenotypic transition is reported to be reversible [36].…”

Reference-based annotation of single cell transcriptomes identifies a profibrotic macrophage niche after tissue injury

“…The most prevalent form, idiopathic pulmonary fibrosis, has a median survival of only 3 years, and approved treatments are limited 2 . With respect to pathogenesis, much attention has focused on fibroblast activation, given the central role of fibroblasts in the deposition of matrix proteins such as collagen [3][4][5][6] . However, the causes of fibroblast activation and proliferation are not fully understood.…”