Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis

Rachana R. Chandran, Yi Xie, Eunate Gallardo-Vara, Taylor Adams, Rolando Garcia-Milian, Inamul Kabir, Abdul Q. Sheikh, Naftali Kaminski, Kathleen A. Martin, Erica L. Herzog and Daniel M. Greif ()
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Rachana R. Chandran: Yale University School of Medicine
Yi Xie: Yale University School of Medicine
Eunate Gallardo-Vara: Yale University School of Medicine
Taylor Adams: Yale University School of Medicine
Rolando Garcia-Milian: Yale University School of Medicine
Inamul Kabir: Yale University School of Medicine
Abdul Q. Sheikh: Yale University School of Medicine
Naftali Kaminski: Yale University School of Medicine
Kathleen A. Martin: Yale University School of Medicine
Erica L. Herzog: Yale University School of Medicine
Daniel M. Greif: Yale University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27499-8

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