Novel fibroblast phenotypes in homeostasis and chronic inflammation: From functions to potential regulators

Fibroblasts are essential components of the stroma, sustaining a variety of tissues and being key to the process of tissue repair after injury. Their role in tissue repair has been attributed to their ability to acquire a contractile, extracellular matrix-producing phenotype known as myofibroblasts. This property is primarily dependent on their response to the pleiotropic cytokine transforming growth factor-β1. Until recently, the potential role of fibroblasts in other homeostatic and disease-related processes was less well understood. Although in vitro studies indicated that fibroblasts are able to respond to and secrete inflammatory mediators, definitive evidence of their contribution to chronic inflammation was limited. However, the emergence of techniques that allow exploration of tissues at the single cell level has challenged the previous paradigms on fibroblast identity and functions, and has led to the discovery of significant diversity, showing the presence of fibroblasts with alternate transcriptional profiles in a variety of tissues. These studies have also suggested potential roles of novel fibroblast subtypes as regulators of epithelial homeostasis and renewal, inflammatory cell infiltration and activation, and antigen presentation. Here, we provide a comprehensive review of the recent literature on fibroblast diversity in the digestive tract, skin, lungs and joints. We also review evidence of their contribution to the regulation of homeostasis and chronic inflammation, as well as their interactions with other cells in various tissue compartments. We discuss evidence of different factors involved in the control of fibroblast function, addressing the role of various cytokines, transcription factors and epigenetic changes, as well as microenvironmental factors, including extracellular matrix stiffness, hypoxia, and metabolic shifts.