Evidence of Fibroblast Heterogeneity and the Role of Fibroblast Subpopulations in Fibrosis

Abstract

This review article highlights the evidence supporting the concept that, like lymphocytes, fibroblasts also consist of subpopulations with unique phenotypes and functions. A new view of the fibroblast is that they are dynamic and consist of subsets which produce cytokines and interact with the immune system. For example, murine lung fibroblasts separated by fluorescence-activated cell sorting on the basis of the thymocyte-1 antigen are heterogeneous in their morphology, expression of surface markers, antigen presentation to T lymphocytes, ability to synthesize collagen, and cytokine production. Human lung fibroblasts have also been found to be heterogeneous in surface marker expression, proliferation, and collagen production. Investigation of pulmonary fibroblast heterogeneity is important since the lung is particularly susceptible to fibrosis induced by chemotherapy and radiation, inhaled particles, systemic autoimmune disease, etc. The inflammatory responses which typically precede fibrotic induction may be controlled by a subset of resident fibroblasts. Another subset may be important for the fibroblast hyperplasia and extensive extracellular matrix production which are hallmarks of fibrosis. In another model system, periodontal fibroblasts, namely those from periodontal ligament (PDL) and gingiva, also reveal heterogeneity. For example, PDL fibroblasts are composed of subpopulations based on collagen production, morphology, and glycogen pools. Subsets of gingival fibroblasts have also been obtained based on receptors for cyclosporin A and C1q. Specific fibroblast subsets may be involved in gingival repair and hyperplasia. Studies comparing fibroblasts from normal skin vs skin involved with scleroderma have found that scleroderma fibroblasts are activated and able to participate in an inflammatory response. How these fibroblasts become activated is unclear, but it is believed that a subset of fibroblasts is selectively recruited by cytokines at the inflammation site. Finally, investigation and identification of fibroblast subsets from various tissues and their interaction with the immune system could lead to strategies to prevent or reverse debilitating and potentially fatal fibrotic development.