Fibroblast Heterogeneity in and Its Implications for Plastic and Reconstructive Surgery: A Basic Science Review

Abstract

Summary: Fibroblasts’ integral role in tissue development, maintenance, and disease represents a fast-growing field of basic science research. Although fibroblasts were long thought to be a homogeneous cell population, recent research has illuminated the unforeseen complexity of these cells, giving rise to the rapidly expanding research field of “fibroblast heterogeneity.” Fibroblasts play a critical role in states of tissue fibrosis such as skin scarring, which affects hundreds of millions of patients annually and causes severe aesthetic, developmental, and functional morbidity. Beyond scarring, major organ fibrosis is an enormous public health concern responsible for nearly half of all deaths in the United States. Because fibrosis is a conserved response to tissue damage in all organs, the study of fibroblasts throughout the body may help us to understand their role in the conditions most relevant to plastic and reconstructive surgery—for instance, skin scarring (eg, from burns, traumatic lacerations, or surgical incisions), “pathological” scarring (hypertrophic scars, keloids), and capsular contracture. Here, we present a basic science review of fibroblast heterogeneity in wound healing, cancer, organ fibrosis, and human dermal architecture. The field of fibroblast heterogeneity is young, and many of the insights discussed have yet to be translated clinically. However, plastic surgeons stand in a unique position to bridge these discoveries into clinical realities. We hope this information can spur readers to consider both what questions in plastic surgery can be studied from the lens of fibroblast heterogeneity, and how these preclinical insights can be translated to improving care of our patients.

Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring

“…Early evidence suggests that ENF-mediated healing after verteporfin treatment leads to recovery of normal skin glands, hair follicles, and matrix ultrastructure through activation of Wnt/Trps1 stem cell and hair follicle development pathways (25). Scar-reducing strategies often entail ablating fibrogenic cell populations, which can potentially impair healing by nonspecifically eliminating necessary cells (5,7,8). Thus, the therapeutic goal of skin regeneration-defined by recovery of secondary elements, ECM structure, and mechanical strength-has remained unachieved.…”

“…); are characterized by fibrotic extracellular matrix (ECM) with dense, parallel fibers (versus the "basketweave" pattern that gives skin its flexibility and strength); and, because of this altered fiber structure, are weaker than unwounded skin. Scarring can cause disfigurement, growth restriction, and permanent functional loss (1-5), ultimately costing the US more than $20 billion every year; the cost worldwide is likely much higher (6,7). A scar-preventing therapy should restore appendages, normal matrix structure, and strength comparable to those of unwounded skin (8,9).…”

Combined Treatment of Monopolar and Bipolar Radiofrequency Increases Skin Elasticity by Decreasing the Accumulation of Advanced Glycated End Products in Aged Animal Skin

“…Delta-like non-canonical notch ligand 1 (Dlk1) is expressed in the dermal fibroblast precursor, reticular fibroblast precursor, and reticular fibroblast [ 51 ]. Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1) are expressed in the dermal fibroblast precursor, papillary dermal fibroblast precursor, and papillary dermal fibroblast [ 51 ]. Fibroblast-specific protein 1 (Fsp1) is expressed in the papillary dermal fibroblast [ 51 ].…”

“…Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1) are expressed in the dermal fibroblast precursor, papillary dermal fibroblast precursor, and papillary dermal fibroblast [ 51 ]. Fibroblast-specific protein 1 (Fsp1) is expressed in the papillary dermal fibroblast [ 51 ].…”

The fibroblast: An emerging key player in thymic T cell selection

“…DPP4 is a useful marker for the detection and isolation of capFbs. DPP4 is reportedly expressed by activated fibroblasts in fibrotic tissues such as the skin of patients with systemic sclerosis as well as in cases of liver fibrosis 79 , 80 , 81 , 82 or the breast implant capsule in patients with capsular contraction. 83 , 84 Genetic ablation or pharmacological inhibition of DPP4 ameliorates fibrosis in mice, indicating that DPP4 activity is important for fibroblast activation and tissue fibrosis.…”