Biology subjects

Meizlish, M. L.

Publications and source records attributed to Meizlish, M. L..

3 recordsLinked to original sources

bioRxiv2023

Macrophages sense ECM mechanics and growth factor availability through cytoskeletal remodeling to regulate their tissue repair program

Tissue resident macrophages play important roles in tissue homeostasis and repair. However, how macrophages monitor and maintain tissue integrity is not well understood. The extracellular matrix (ECM) is a key structural and organizational component of all tissues. Here, we find that macrophages sense the mechanical properties of the ECM in order to regulate a specific tissue repair program. We show that macrophage mechanosensing is mediated by cytoskeletal remodeling and can be performed in three-dimensional environments through a non-canonical, integrin-independent mechanism analogous to amoeboid migration. We find that these cytoskeletal dynamics also integrate biochemical signaling by CSF1 and ultimately regulate chromatin accessibility to control the mechanosensitive gene expression program. This study suggests a distinct mode of ECM mechanosensing and growth factor signaling through which macrophages may regulate tissue repair and fibrosis.

immunology↗

bioRxiv2022

Microenvironmental sensing by fibroblasts controls macrophage population size

Animal tissues are comprised of 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-{beta} target genes are both regulated by cell density. We found YAP1, the transcriptional co-activator 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. Significance StatementCollections of distinct cell types constitute animal tissues. To perform their unique functions, each cell type must exist in the correct number and proportion in a given tissue compartment. However, many of the mechanisms regulating and coordinating cell population sizes remain enigmatic. Our study characterizes two different modes of population size control, utilized by two ubiquitous cell types, macrophages and fibroblasts. Macrophage populations are more sensitive to the presence of growth factors in the environment and fibroblasts are more sensitive to space limitations. Intriguingly, space-sensing mechanisms in fibroblasts directly control the production of growth factor for macrophages and thus macrophage numbers. This link suggests a mechanism by which macrophage compartment size is controlled by stromal cells according to the microenvironment.

immunology↗

bioRxiv2021

Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis

Tissue repair is disturbed in fibrotic diseases like systemic sclerosis (SSc), where the deposition of large amounts of extracellular matrix components such as collagen interferes with organ function. LAIR-1 is an inhibitory collagen receptor highly expressed on tissue immune cells. We questioned whether in SSc, impaired LAIR-1-collagen interaction is contributing to the ongoing inflammation and fibrosis. We found that SSc patients do not have an intrinsic defect in LAIR-1 expression or function. Instead, fibroblasts from SSc patients deposit disorganized collagen products in vitro, which are dysfunctional LAIR-1 ligands. This can be mimicked in healthy fibroblasts stimulated by soluble factors that drive inflammation and fibrosis in SSc and is dependent of matrix metalloproteinases and platelet-derived growth factor receptor signaling. In support of a non-redundant role of LAIR-1 in the control of fibrosis, we found that LAIR-1-deficient mice have increased skin fibrosis in response to repeated injury and in the bleomycin mouse model for SSc. Thus, LAIR-1 represents an essential control mechanism for tissue repair. In fibrotic disease, excessive collagen degradation may lead to a disturbed feedback loop. The presence of functional LAIR-1 in patients provides a therapeutic opportunity to reactivate this intrinsic negative feedback mechanism in fibrotic diseases.

immunology↗