Environmental sensing by fibroblasts regulates tissue composition

Diverse cell types comprise animal tissues. However, the mechanisms controlling the number of each cell type within tissue compartments remain poorly understood. Here, we reported 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-b signaling are both regulated by cell density. We found YAP1, the transcriptional activator of the Hippo signaling pathway, directly regulate expression of Csf1, the lineage-specific growth factor for macrophages, through binding of YAP1 to a conserved 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 pressure 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.