Extracellular matrix regulation of fibroblast function: redefining our perspective on skin aging

Abstract

The dermal extracellular matrix (ECM) comprises the bulk of skin and confers strength and resiliency. In young skin, fibroblasts produce and adhere to the dermal ECM, which is composed primarily of type I collagen fibrils. Adherence allows fibroblasts to spread and exert mechanical force on the surrounding ECM. In this state, fibroblasts display a "youthful" phenotype characterized by maintenance of the composition and structural organization of the dermal ECM. During aging, fibroblast-ECM interactions become disrupted due to fragmentation of collagen fibrils. This disruption causes loss of fibroblast spreading and mechanical force, which inextricably lead to an "aged" phenotype; fibroblasts synthesize less ECM proteins and more matrix-degrading metalloproteinases. This imbalance of ECM homeostasis further drives collagen fibril fragmentation in a self-perpetuating cycle. This article summarizes age-related changes in the dermal ECM and the mechanisms by which these changes alter the interplay between fibroblasts and their extracellular matrix microenvironment that drive the aging process in human skin.

Keywords: Aging; CCN1; Collagen; MMP-1; Skin.

Fig. 1

Fragmentation of collagen fibrils within dermis of aged or photoaged skin causes collapse of fibroblasts. a Transmission electron micrograph of fibroblast (colored pink for clarity) within dermis of sun-protected skin from young adult. Note extended cytoplasm (X) close proximity to abundant collagen fibrils (arrows) (nucleus (N), original magnification ×2000). b Transmission electron micrograph of fibroblast (colored pink for clarity) within dermis of photodamaged skin. Note collapse of cytoplasm inward toward nucleus (N) and lack of adjacent collagen fibrils (asterisks) (original magnification ×2000). c Scanning electron micrograph of collagen fibrils in young adult skin. Note densely packed long fibrils, without apparent fragmentation (original magnification ×10,000). d Scanning electron micrograph of collagen fibrils in photodamaged human skin. Note large gaps and numerous fragmented fibrils (original magnification ×8000). Inset shows higher magnification of fragmented ends of fibrils (arrows) (original magnification ×12,500). Reprinted with permission from Fisher et al. Arch Dermatol. ;144(5):666–672. 10.1001/archderm.144.5.666

Fig. 2

Schematic diagram of a collagen fibril illustrating the distinct triple helical structure of the α-chains. Representative portions of three individual α-chains, each with the triple amino acid repeat Gly-X-Y, are shown in the magnified section. Each chain is comprised of a glycine (black), proline (position ‘X,’ red), and hydroxyproline (position ‘Y,’ blue) residue. Hydrogen bonds (dashed black lines) between the N–H of glycine on each chain and the carbonyl of proline on an adjacent chain establish the triple helix

Fig. 3

Enzyme-mediated modifications of collagen molecules. Intracellular processing includes the conversion of lysine into hydroxylysine via lysyl hydroxylase (red), while extracellular lysly oxidase (orange) is required to convert the amine moeity of lysine (or hydroxylysine) into an aldehyde functional group

Fig. 4

The mechanism for lysinonorleucine crosslink formation between collagen/elastin fibrils. The coupling of protonated Lys (or Hyl) with Lys^ald (or Hyl^ald) occurs spontaneously following aldehyde-generation via LOX. Reduction of the reversible Schiff base intermediate generates an irreversible lysinonorleucine crosslink junction

Fig. 5

Schematic illustration of the consequences of chronological- and photo-aging on intracellular pathways that regulate collagen homeostasis. The overall impact of time and UV irradiation on dermal fibroblasts is upregulation of MMPs, resulting in collagen degradation and concomitant downregulation of collagen synthesis. ROS (reactive oxygen species), PTP (protein tyrosine phosphatases), RTK (receptor tyrosine kinase), Grb2 (growth factor receptor-bound protein 2), Sos1 (son of sevenless homolog 1), MAPK (mitogen activated protein kinase), AP-1 (activated protein 1), CCN1 (cysteine-rich protein 61), MMP (matrix metalloprotease), TNF- α (tumor necrosis factor alpha), GzmB (granzyme B), TGF-β (transforming growth factor beta)