Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis
Abstract
During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate excess myofibroblasts and extracellular matrix; herein, we focus on signaling in the mesenchyme. Our studies indicate that platelet-derived growth factor receptor (PDGFR)-β+ cells are the predominant source of myofibroblasts and Kruppel-like factor (KLF) 4 is upregulated in PDGFR-β+ cells, inducing TGFβ pathway signaling and fibrosis. In fibrotic lung patches, KLF4 is down-regulated, suggesting KLF4 levels decrease as PDGFR-β+ cells transition into myofibroblasts. In contrast to PDGFR-β+ cells, KLF4 reduction in α-smooth muscle actin (SMA)+ cells non-cell autonomously exacerbates lung fibrosis by inducing macrophage accumulation and pro-fibrotic effects of PDGFR-β+ cells via a Forkhead box M1 to C-C chemokine ligand 2—receptor 2 pathway. Taken together, in the context of lung fibrosis, our results indicate that KLF4 plays opposing roles in PDGFR-β+ cells and SMA+ cells and highlight the importance of further studies of interactions between distinct mesenchymal cell types.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 10, 2021
- Source ID
- 10.1038/s41467-021-27499-8
Entities
People
- Abdul Q. Sheikh
- Daniel M. Greif
- Erica L Herzog
- Eunate Gallardo-Vara
- Inamul Kabir
- Kathleen A. Martin
- Naftali Kaminski
- Rachana R. Chandran
- Rolando Garcia-Milian
- Taylor Adams
- Yi Xie
Organizations
- American Heart Association
- National Heart, Lung, and Blood Institute
- United States Department of Defense