Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis
| Autor: | 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, Daniel M. Greif |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Science Down-Regulation General Physics and Astronomy Pathogenesis Article General Biochemistry Genetics and Molecular Biology Receptor Platelet-Derived Growth Factor beta Kruppel-Like Factor 4 Mice stomatognathic system Transforming Growth Factor beta Animals Humans Myofibroblasts Lung Cell Proliferation Respiratory tract diseases Multidisciplinary fungi Mesenchymal Stem Cells Lung Injury General Chemistry Fibroblasts Fibrosis Extracellular Matrix Mice Inbred C57BL Disease Models Animal embryonic structures cardiovascular system Female sense organs biological phenomena cell phenomena and immunity Signal Transduction |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. The pluripotency factor KLF4 has been described as pro-fibrotic or anti-fibrotic in various diseases. Herein, the authors show that during lung fibrosis, these distinct effects can be attributed to mesenchymal cell-type specific functions of KLF4. |
| Databáze: | OpenAIRE |
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