Stc1-expressing myofibroblasts are a developmentally distinct lineage cleared through intrinsic apoptosis in the...

Lung myofibroblasts are necessary for early postnatal alveolar growth and develop again during pathological fibrosis. Determining the unique contributions of multiple myofibroblast lineages to development and disease is hampered by a lack of genetic tools to distinguish between them. In this study, we generated a Stc1 ^CreERT2 mouse line that faithfully labels the developmentally transient secondary crest myofibroblasts (SCMF) and distinguishes SCMFs from alveolar duct myofibroblasts (DMF) and smooth muscle. SCMF populations expand by clonal proliferation of Stc1 -expressing progenitors and contract by apoptosis. We deleted the intrinsic apoptosis effectors Bax and Bak1 in the Stc1-lineage, which prevented SCMF clearance during alveologenesis. Single-cell RNA-seq revealed that residual Stc1-lineage cells lacking Bax and Bak1 lose myofibroblast identity but express a combination of SCMF and DMF marker genes. Embryonic lineage tracing identified that SCMFs and DMFs have distinct progenitor populations with unique niches, and genetic activation of developmentally important signaling pathways could not interconvert these lineages. These findings establish Stc1-lineage SCMFs as a discrete population, developmentally divergent from DMFs, and define their life cycle in isolation from other myofibroblast lineages.