| Autor: |
Zhou X; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510., Franklin RA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510., Adler M; Broad Institute of MIT and Harvard, Cambridge, MA 02142., Carter TS; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139., Condiff E; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510., Adams TS; Pulmonary Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06510., Pope SD; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510.; HHMI, Yale University School of Medicine, New Haven, CT 06510., Philip NH; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510., Meizlish ML; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510., Kaminski N; Pulmonary Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06510., Medzhitov R; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510.; HHMI, Yale University School of Medicine, New Haven, CT 06510. |
| Abstrakt: |
Animal tissues comprise diverse cell types. However, the mechanisms controlling the number of each cell type within tissue compartments remain poorly understood. Here, we report that different cell types utilize distinct strategies to control population numbers. Proliferation of fibroblasts, stromal cells important for tissue integrity, is limited by space availability. In contrast, proliferation of macrophages, innate immune cells involved in defense, repair, and homeostasis, is constrained by growth factor availability. Examination of density-dependent gene expression in fibroblasts revealed that Hippo and TGF-β target genes are both regulated by cell density. We found YAP1, the transcriptional coactivator of the Hippo signaling pathway, directly regulates expression of Csf1 , the lineage-specific growth factor for macrophages, through an enhancer of Csf1 that is specifically active in fibroblasts. Activation of YAP1 in fibroblasts elevates Csf1 expression and is sufficient to increase the number of macrophages at steady state. Our data also suggest that expression programs in fibroblasts that change with density may result from sensing of mechanical force through actin-dependent mechanisms. Altogether, we demonstrate that two different modes of population control are connected and coordinated to regulate cell numbers of distinct cell types. Sensing of the tissue environment may serve as a general strategy to control tissue composition. |
