Keloid progression: a stiffness gap hypothesis

Abstract

Keloids are fibroproliferative skin disorders characterised clinically by continuous horizontal progression and post-surgical recurrence and histologically by the accumulation of collagen and fibroblast ingredients. Till now, their aetiology remains clear, which may cover genetic, environmental and metabolic factors. Evidence in the involvement of local mechanics (e.g. predilection site and typical shape) and the progress in mechanobiology have incubated our stiffness gap hypotheses in illustrating the chronic but constant development in keloid. We put forward that the enlarged gap between extracellular matrix (ECM) stiffness and cellular stiffness potentiates keloid progression. Matrix stiffness itself provides organisational guidance cues to regulate the mechanosensitive resident cells (e.g. proliferation, migration and apoptosis). During this dynamic process, the ECM stiffness and cell stiffness are not well balanced, and the continuously enlarged stiffness gap between them potentiates keloid progression. The cushion factors, such as prestress for cell stiffness and topology for ECM stiffness, serve as compensations, the decompensation of which aggravates keloid development. It can well explain the typical shape of keloids, their progression in a horizontal but not vertical direction and the post-surgical recurrence, which were evidenced by our clinical cases. Such a stiffness gap hypothesis might be bridged to mechanotherapeutic approaches for keloid progression.

Keywords: Extracellular cell matrix stiffness; Keloid; Mechanobiology; Mechanoresponsiveness; Scar pathology.

Figure 1

Typical shapes of keloids. Clinically, in the predilection sites of keloids, such as chest or scapula, that are constantly exposed to cutaneous stretch, the typical shapes of keloids are butterfly, crab's claw or dumbbell, which are largely determined by the local mechanics on the skin. A. Butterfly in the chest B. Crab's claw in the chest C. Dumbbell on the shoulder

Figure 2

Stiffness gap hypothesis, the balance between cell and extracellular matrix (ECM) stiffness and their cushion factors. Cutaneous resident cells in keloids can sense (mechanosensitivity) and respond (mechanoresponsiveness) to the stiffness gap between ECM and themselves by mechanotransduction where intracellular biochemistry and gene expression leads to cell function changes. The input stiffness gap can somewhat be cushioned by cellular factors such as prestress, structural organisation and composition, as well as ECM factors, such as its topology, thickness and composition. If failed, the tilted balance induced by enlarged stiffness gap between ECM and cell will guide the keloid progression through the output of changes in cellular functions, such as reduced apoptosis and increased proliferation.

Figure 3

Molecular‐ and tissue‐level illustration of stiffness gap hypothesis in keloid progression. At the tissue level, during the vertical advancement of keloids, the sudden drop of the extracellular matrix (ECM) stiffness from collagen type I in the dermis to the fat in the underlying subcutaneous level will reduce the stiffness gap of ECM and cells. Although the dermis and subcutaneous adipose are different in many aspects, such as niche components, we believe that the stiffness gap contributes, at least partially, to the confinement of keloid progress. Together with the reactive compensations from cells, vertical keloid progression stops beyond the subcutaneous layer. At the molecular level, the mechanosignalling pathways involved in pathological scarring cover transforming growth factor‐β, integrin and G proteins and may provide mechanobiological evidence for stiffness gap hypothesis in explaining keloid progression.

Figure 4

Chest keloid case demonstrating the change in local extracellular matrix (ECM) stiffness by stretching anisotropy and subsequent shape modification. The patient was an 84‐year‐old male with a chest keloid in the shape of a butterfly. Two years ago, he accidently broke the keloid from the central, and the wound healed automatically without medical intervention. After that, the right half‐butterfly on his dominant‐hand side progressed as usual under the vectorial stretching and the subsequent anisotropy of ECM stiffness, while the left half‐butterfly ameliorated. Consequently, the butterfly was not symmetrical any longer, with the left half much smaller than the right half.