Dataset Information

Principles of Cell Circuits for Tissue Repair and Fibrosis.

ABSTRACT: Tissue repair is a protective response after injury, but repetitive or prolonged injury can lead to fibrosis, a pathological state of excessive scarring. To pinpoint the dynamic mechanisms underlying fibrosis, it is important to understand the principles of the cell circuits that carry out tissue repair. In this study, we establish a cell-circuit framework for the myofibroblast-macrophage circuit in wound healing, including the accumulation of scar-forming extracellular matrix. We find that fibrosis results from multistability between three outcomes, which we term "hot fibrosis" characterized by many macrophages, "cold fibrosis" lacking macrophages, and normal wound healing. This framework clarifies several unexplained phenomena including the paradoxical effect of macrophage depletion, the limited time-window in which removing inflammation leads to healing, and why scar maturation takes months. We define key parameters that control the transition from healing to fibrosis, which may serve as potential targets for therapeutic reduction of fibrosis.

SUBMITTER: Adler M

PROVIDER: S-EPMC7005469 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Principles of Cell Circuits for Tissue Repair and Fibrosis.

Adler Miri M Mayo Avi A Zhou Xu X Franklin Ruth A RA Meizlish Matthew L ML Medzhitov Ruslan R Kallenberger Stefan M SM Alon Uri U

iScience 20200116 2

Tissue repair is a protective response after injury, but repetitive or prolonged injury can lead to fibrosis, a pathological state of excessive scarring. To pinpoint the dynamic mechanisms underlying fibrosis, it is important to understand the principles of the cell circuits that carry out tissue repair. In this study, we establish a cell-circuit framework for the myofibroblast-macrophage circuit in wound healing, including the accumulation of scar-forming extracellular matrix. We find that fibr ...[more]

PMID: 32058955

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Project description:For the vast majority of genes in sequenced genomes, there is limited understanding of how they are regulated. Without such knowledge, it is not possible to perform a quantitative theory-experiment dialogue on how such genes give rise to physiological and evolutionary adaptation. One category of high-throughput experiments used to understand the sequence-phenotype relationship of the transcriptome is massively parallel reporter assays (MPRAs). However, to improve the versatility and scalability of MPRA pipelines, we need a "theory of the experiment" to help us better understand the impact of various biological and experimental parameters on the interpretation of experimental data. These parameters include binding site copy number, where a large number of specific binding sites may titrate away transcription factors, as well as the presence of overlapping binding sites, which may affect analysis of the degree of mutual dependence between mutations in the regulatory region and expression levels. Here, we develop a computational pipeline that makes it possible to systematically explore how each biological and experimental parameter controls measured MPRA data. Specifically, we use equilibrium statistical mechanics in conjunction with predictive base-pair resolution energy matrices to predict expression levels of genes with mutated regulatory sequences and subsequently use mutual information to interpret synthetic MPRA data including recovering the expected binding sites. Our simulations reveal important effects of the parameters on MPRA data and we demonstrate our ability to optimize MPRA experimental designs with the goal of generating thermodynamic models of the transcriptome with base-pair specificity. Further, this approach makes it possible to carefully examine the mapping between mutations in binding sites and their corresponding expression profiles, a tool useful not only for better designing MPRAs, but also for exploring regulatory evolution.

Dataset Information

Principles of Cell Circuits for Tissue Repair and Fibrosis.

Publications

Principles of Cell Circuits for Tissue Repair and Fibrosis.

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