Stc1-expressing myofibroblasts are a developmentally distinct lineage cleared through apoptosis in the neonatal lung

TL;DR

Researchers identified a unique type of lung myofibroblast that appears briefly in early life and is cleared through cell death, using a new genetic tool.

Contribution

A novel Stc1CreERT2 mouse line was developed to distinguish a transient myofibroblast lineage in the neonatal lung.

Findings

Stc1-expressing myofibroblasts (SCMFs) expand through clonal proliferation and are cleared by apoptosis.

Deleting Bax and Bak1 in the Stc1 lineage prevents SCMF clearance during alveologenesis.

SCMFs and ductal myofibroblasts (DMFs) arise from distinct embryonic progenitors and cannot be interconverted.

Abstract

Lung myofibroblasts are necessary for early postnatal alveolar growth. The unique contributions of individual myofibroblast lineages to alveolar development are unresolved by existing genetic tools. We generated a Stanniocalcin-1 (Stc1)CreERT2 mouse line that labels the developmentally transient secondary crest myofibroblasts (SCMFs), distinguishing them from alveolar duct myofibroblasts (DMFs) and smooth muscle. SCMFs expand through clonal proliferation of Stc1-expressing progenitors and are cleared by apoptosis. Deleting the apoptosis effectors Bax and Bak1 in the Stc1 lineage prevented SCMF clearance during alveologenesis. Single-cell RNA sequencing showed that surviving Stc1-lineage cells lose myofibroblast identity while co-expressing SCMF and DMF markers. Embryonic lineage tracing identified distinct progenitors for SCMFs and DMFs, and genetic activation of Hedgehog (Hh) or Wnt signaling pathways failed to interconvert these lineages. These findings establish Stc1-lineage SCMFs as a discrete, developmentally divergent population and define their life cycle independent of other myofibroblast lineages.

Snitow et al. generated a novel Stc1CreERT2 mouse line to label alveolar secondary crest myofibroblasts (SCMFs), distinguishing them from other mesenchymal lineages in the lung. They found that transient SCMFs are cleared by intrinsic apoptosis and arise from embryonic progenitors distinct from those of ductal myofibroblasts (DMFs).

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