What’s in a name? On fibroblast phenotype and nomenclature

Abstract

Fibroblasts have long been recognized as important stromal cells, playing key roles in synthesizing and maintaining the extracellular matrix, but historically were treated as a relatively uniform cell type. Studies in recent years have revealed a surprising level of heterogeneity of fibroblasts across tissues, and even within organs such as the skin and heart. This heterogeneity may have functional consequences, including during stress and disease. While the field has moved forward quickly to begin to address the scientific import of this heterogeneity, the descriptive language used for these cells has not kept pace, particularly when considering the phenotype changes that occur as fibroblasts convert to myofibroblasts in response to injury. We discuss here the nature and sources of the heterogeneity of fibroblasts, and review how our understanding of the complexity of the fibroblast to myofibroblast phenotype conversion has changed with increasing scrutiny. We propose that the time is opportune to reevaluate how we name and describe these cells, particularly as they transition to myofibroblasts through discrete stages. A standardized nomenclature is essential to address the confusion that currently exists in the literature as to the usage of terms like myofibroblast and the description of fibroblast phenotype changes in disease.

Fibroblast‐mediated intercellular crosstalk in the healthy and diseased heart

“…During embryonic development, cardiac fibroblasts (identified by the expression of PDGFRα, TCF21 [2,3]) arise from cardiac endothelial cells, the epicardium, and the neural crest [2,11,12,19]. Upon stimulation by inflammatory or profibrotic cytokines (e.g., TGFβ), cardiac fibroblasts transit to an activated state, which can be identified using marker genes and regulators such as TGFβ, POSTN, SMAD 2/3/4 [24,25,27–29], and can further differentiate to myofibroblasts that show a strong contractile and matrix‐secretory phenotype [30].…”

Cardiac Fibroblast to Myofibroblast Phenotype Conversion—An Unexploited Therapeutic Target

“…The ECM is synthesized and maintained by stromal cells embedded throughout the tissue or organ. Most often, these cells are fibroblasts, although there is significant ongoing debate regarding the nature of fibroblasts, their nomenclature and their heterogeneity across tissue types [2,10,11,12]. Other cell types may also contribute to ECM synthesis, such as hepatic stellate cells, vascular smooth muscle cells and fibrocytes, depending on the particular tissue in question [12].…”

“…Most often, these cells are fibroblasts, although there is significant ongoing debate regarding the nature of fibroblasts, their nomenclature and their heterogeneity across tissue types [2,10,11,12]. Other cell types may also contribute to ECM synthesis, such as hepatic stellate cells, vascular smooth muscle cells and fibrocytes, depending on the particular tissue in question [12]. A common theme that has emerged is that, while ECM and the stromal cells that generate it may be linked by a common underlying role, the highly variable mechanical requirements of different tissue types has resulted in significant heterogeneity in these stromal cells as well as in the specific ECM that they produce.…”

Cancer-associated fibroblasts promote oral squamous cell carcinoma progression through LOX-mediated matrix stiffness

“…The tumor microenvironment (TME), a complex meshwork of extracellular matrix (ECM) macromolecules, plays an important role in tumor progression. As a main component of TME, cancer-associated fibroblasts (CAFs) are of great importance for ECM production and interstitial tissue remodeling in the disturbed homeostasis [ 5 ], which can induce stiffness and hypoxia in the matrix [ 6 ]. Matrix stiffness is one of the most important biomechanical characteristics of TME faced by cancer cells and stromal cells.…”