Fibroblast heterogeneity: implications for human disease

Abstract

Fibroblasts synthesize the extracellular matrix of connective tissue and play an essential role in maintaining the structural integrity of most tissues. Researchers have long suspected that fibroblasts exhibit functional specialization according to their organ of origin, body site, and spatial location. In recent years, a number of approaches have revealed the existence of fibroblast subtypes in mice. Here, we discuss fibroblast heterogeneity with a focus on the mammalian dermis, which has proven an accessible and tractable system for the dissection of these relationships. We begin by considering differences in fibroblast identity according to anatomical site of origin. Subsequently, we discuss new results relating to the existence of multiple fibroblast subtypes within the mouse dermis. We consider the developmental origin of fibroblasts and how this influences heterogeneity and lineage restriction. We discuss the mechanisms by which fibroblast heterogeneity arises, including intrinsic specification by transcriptional regulatory networks and epigenetic factors in combination with extrinsic effects of the spatial context within tissue. Finally, we discuss how fibroblast heterogeneity may provide insights into pathological states including wound healing, fibrotic diseases, and aging. Our evolving understanding suggests that ex vivo expansion or in vivo inhibition of specific fibroblast subtypes may have important therapeutic applications.

Figure 1. Structure of murine dorsal skin.

The skin has two layers, the epidermis and the dermis. The epidermis is a stratified squamous epithelium with associated adnexal structures such as hair follicles and sebaceous glands. It is separated from the underlying connective tissue, the dermis, by a basement membrane (red). The three dermal layers are the papillary dermis (PD), reticular dermis (RD), and hypodermis/white adipose tissue. The dermal papilla and arrector pili muscle constitute two specialized populations of dermal mesenchymal cells. Adapted with permission from Science (143).

Figure 2. Comparison of human and murine skin.

The interfollicular epidermis and dermis are thicker in human than in mouse skin. In most body sites mice possess a higher density of hair follicles. In human skin the boundary between the epidermis and dermis undulates, whereas it is flat in mouse skin. Adapted with permission from Cold Spring Harbor Perspectives in Biology (4).

Figure 3. Mouse dermal fibroblast lineages.

Dermal fibroblasts derive from common fibroblast progenitor cells and differentiate into specific lineages by postnatal day 2 (P2). These subtypes display distinct functions. For example, papillary fibroblasts are essential in the coordination of the hair cycle and the formation of hair follicles after injury, and reticular fibroblasts mediate early wound repair responses. Adapted with permission from Trends in Cell Biology (6). APM, arrector pili muscle.