Fibroblast Memory in Development, Homeostasis and Disease

Abstract

Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their role in remodelling the extracellular matrix, however more recently they have been recognised as a functionally highly diverse cell population that constantly responds and adapts to their environment. Biological memory is the process of a sustained altered cellular state and functions in response to a transient or persistent environmental stimulus. While it is well established that fibroblasts retain a memory of their anatomical location, how other environmental stimuli influence fibroblast behaviour and function is less clear. The ability of fibroblasts to respond and memorise different environmental stimuli is essential for tissue development and homeostasis and may become dysregulated in chronic disease conditions such as fibrosis and cancer. Here we summarise the four emerging key areas of fibroblast adaptation: positional, mechanical, inflammatory, and metabolic memory and highlight the underlying mechanisms and their implications in tissue homeostasis and disease.

Keywords: biological memory; cancer; cell fate; epigenetic modification; fibroblasts; fibrosis; inflammation; mechanical stress; metabolism; positional identity; wound healing.

Figure 1

Mechanisms of biological memory: memory in cells is maintained on several levels, including direct modifications to DNA, changes to histone proteins to alter DNA accessibility, sustained expression of DNA binding factors and nuclear components, increased abundance or activity of cytoplasmic components, such as miRNAs, metabolites and signalling molecules, and through cell surface receptors sensing autocrine and paracrine signals and direct cell-cell and cell-ECM contacts. TF, transcription factor.

Figure 2

Types of fibroblast memory: (a) positional memory is established during development and is largely driven by Hox gene expression. The expression of region specific Hox genes is maintained by autoregulatory loops, modifications to DNA and histones and by ncRNA inhibiting expression of specific Hox genes; (b) mechanical memory: fibroblasts are linked to the external mechanical environment of the ECM by integrins and other adhesion receptors. Mechanical strain transmitted via the cytoskeleton can directly influence chromatin accessibility and gene transcription. Beside chromatin modifications, mechanical memory is maintained through expression of miRNAs (e.g., miR-21), sustained TF activity such as NFκB and YAP/TAZ, and positive feedback loops such as contraction induced release of latent TGF-β from the ECM; (c) inflammatory memory: fibroblasts sense the inflammatory state through pattern recognition and cytokine receptors. Memory is maintained through modifications to DNA and histones, sustained TF and signalling pathway activity, such as the JAK/STAT pathway, and possibly through miRNAs; (d) metabolic memory in fibroblasts is maintained by modifications to DNA and histones, sustained TF activity, an autocrine TGF-β feedback loop and positive feedback involving altered mitochondrial signalling and cellular metabolite levels.