Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

Abstract

SummaryThe structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix (ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three‐dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down‐regulates TGF‐β type II receptor (TβRII) and thus impairs TGF‐β/Smad signaling pathway. Both TβRII mRNA and protein were decreased, resulting in 90% loss of TGF‐β binding to fibroblasts. Down‐regulation of TβRII was associated with significantly decreased phosphorylation, DNA‐binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3‐regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2). Restoration of TβRII significantly increased TGF‐β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of TβRII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of TβRII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging.

Oxidative Stress and Human Skin Connective Tissue Aging

“…Restoration of ROS/cell size-induced loss of TβRII expression significantly increases the TGF-β induction of Smad3 phosphorylation and stimulation of ECM production. Furthermore, ROS/cell size-induced loss of TβRII and ECM production is nearly completely reversed by inhibiting ROS generation [34] and restoring cell size [25].…”

“…In human skin, dermal fibroblasts, the major collagen-producing cells, are responsible for the homeostasis of dermal connective tissue. Dermal fibroblasts reside in a collagenous microenvironment and intimately interact with collagen fibrils, and thus maintain normal cell shape and mechanical tension for function [20,25]. As such, collagen is a critical determinant for cell shape and mechanical tension, which is known to regulate many cellular functions [26].…”

“…Interestingly, both ROS and reduced dermal fibroblast size/mechanical tension specifically down-regulate TβRII, and thus impair the TGF-β/Smad signaling pathway and ECM production [25,34]. ROS/cell size-specific down-regulation of TβRII is associated with significantly decreased phosphorylation, DNA-binding, and transcriptional activity of its key down-stream effector Smad3, as well as reduced expression of Smad3-regulated type I collagen, fibronectin and CTGF/CCN2.…”

Resection force analysis of 1 and 2 mm punch biospies combined with rotation on temperature-controlled cadaver skin use for the acquisition of full skin islets for skin transplantation

“…Again, the result was that the skin reaches biological maturity at an early age (15 -20 years) at which point it then starts to age [9]. Recent studies support the idea that collagen plays a role in the aging of the skin [10][11][12]. In addition to the work on the mechanical properties of the skin, investigations were also carried out in the past on the forces which were required to penetrate the skin and other materials with differently shaped objects.…”

In Situ Atomic Force Microscopy Studies on Nucleation and Self-Assembly of Biogenic and Bio-Inspired Materials

“…For example, by (nano) indenting or stretching materials, their mechanical properties, such as adhesion and elasticity, can be precisely measured and mapped on the surface [100][101][102][103][104]. AFMbased nanoindentation and force spectroscopy has been applied to study many biological and bioinspired systems, including bacterial adhesive material [105], viruses [106][107][108][109][110][111][112][113][114][115][116][117][118], proteins [119][120][121][122][123][124][125], nucleic acids [126][127][128][129][130], cells [131][132][133], and plant cell walls [134]. The mechanical properties of the materials can be connected to the processes of material nucleation and self-assembly [100][101][102][103].…”