Dissecting Fibroblast Heterogeneity in Health and Fibrotic Disease

Abstract

Purpose of review: Fibroblasts, the major cell population in all connective tissues, are best known for their role in depositing and maintaining the extracellular matrix. Recently, numerous specialised functions have been discovered revealing unpredicted fibroblast heterogeneity. We will discuss this heterogeneity, from its origins in development to alterations in fibrotic disease conditions.

Recent findings: Advances in lineage tracing and single-cell transcriptional profiling techniques have revealed impressive diversity amongst fibroblasts in a range of organ systems including the skin, lung, kidney and heart. However, there are major challenges in assimilating the findings and understanding their functional significance. Certain fibroblast subsets can make specific contributions to healthy tissue functioning and to fibrotic disease processes; thus, therapeutic manipulation of particular subsets could be clinically beneficial. Here we propose that four key variables determine a fibroblast's phenotype underpinning their enormous heterogeneity: tissue status, regional features, microenvironment and cell state. We review these in different organ systems, highlighting the importance of understanding the divergent fibroblast properties and underlying mechanisms in tissue fibrosis.

Keywords: Cell heterogeneity; Fibroblast; Fibrosis; Myofibroblast; Single-cell transcriptomics; Tissue injury.

Fig. 1

Strategies for fibroblast stratification. a Layers of the fibroblast phenotype. Within a tissue, the diversity of the fibroblast population (e.g. as identified by single-cell RNA-seq) will be the combined reflection of the tissue state, regional/anatomical variations, local heterogeneity (microenvironment) and cellular state. b Discovering how different tissue states influence fibroblast heterogeneity. Single-cell RNA-seq generally starts with adult homeostatic tissue to define fibroblast heterogeneity at a local level (e.g. tissue biopsy; highlighted in grey). These efforts have revealed subpopulations with distinct functionality that are predominately in a quiescent state. How these lineages develop is variable between organ systems, but involves significant proliferation of a pool of multipotent progenitors that ultimately differentiate into specialised subsets. Upon tissue injury, fibroblasts become activated and may transiently change their relative abundances and functionality. New subpopulations (e.g. myofibroblast) may appear during this process from one or several precursors. More significant and persistent changes in fibroblast heterogeneity have been observed in fibrotic disease conditions (e.g. accumulation and dominance of continuously active myofibroblasts, which themselves are diverse). With age, fibroblast abundance and diversity decline, which may impair organ function or ability to regenerate. Cell size indicates fibroblast subpopulation abundance and the colouring illustrates different cellular states within a functionally distinct population. schematic provides some illustrative examples only that is based upon current literature but do not represent a specific organ system.