Epithelial mechanobiology, skin wound healing, and the stem cell niche

Abstract

Skin wound healing is a vital process that is important for re-establishing the epithelial barrier following disease or injury. Aberrant or delayed skin wound healing increases the risk of infection, causes patient morbidity, and may lead to the formation of scar tissue. One of the most important events in wound healing is coverage of the wound with a new epithelial layer. This occurs when keratinocytes at the wound periphery divide and migrate to re-populate the wound bed. Many approaches are under investigation to promote and expedite this process, including the topical application of growth factors and the addition of autologous and allogeneic tissue or cell grafts. The mechanical environment of the wound site is also of fundamental importance for the rate and quality of wound healing. It is known that mechanical stress can influence wound healing by affecting the behaviour of cells within the dermis, but it remains unclear how mechanical forces affect the healing epidermis. Tensile forces are known to affect the behaviour of cells within epithelia, however, and the material properties of extracellular matrices, such as substrate stiffness, have been shown to affect the morphology, proliferation, differentiation and migration of many different cell types. In this review we will introduce the structure of the skin and the process of wound healing. We will then discuss the evidence for the effect of tissue mechanics in re-epithelialisation and, in particular, on stem cell behaviour in the wound microenvironment and in intact skin. We will discuss how the elasticity, mechanical heterogeneity and topography of the wound extracellular matrix impact the rate and quality of wound healing, and how we may exploit this knowledge to expedite wound healing and mitigate scarring.

Niche interactions in epidermal stem cells

“…As wound healing is a critical process that re-establishes the epithelial barrier following disease or injury, poor wound healing increases infection risk, causes patient morbidity, and may lead to the scar formation. If there is a defect in the stem cell niche, wound repair could be delayed by the abnormal response of stem cells to injury [5] . Thus, understanding how to recreate the stem cell niche is key to regenerative medicine applications.…”

“…Thus, the interaction between stem cell-associated integrins and the ECM may be important in shaping the epidermal stem cell niche. In addition to the ECM and integrins, growth factors or mechanobiological factors can also affect stem cell fate [4,5] . Furthermore, low oxygen tensions (hypoxia) are necessary to maintain undifferentiated stem cell phenotypes, and also influence proliferation and stem cell fate [6] .…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…Both extrinsic and intrinsic forces contribute to tissue morphogenesis, homeostasis, and regeneration and affect cell shape, proliferation, and migration (Evans et al 2013). Sensing and transmitting forces depend to a large extent on tight interactions between cell adhesion complexes and the cytoskeleton.…”

P75 neurotrophin receptor activates epidermal stem cell differentiation via ERK, JNK and AKT pathways

“…p75NTR serves as a low-affnity receptor to mediate diverse functions [9]. Generally, p75NTR is proteolytically cleaved by γ-secretase to generate intracellular domain after ligand activation [10,11]. It is reported that p75NTR interacts with a variety of proteins [12] that in turn induce different pathways [13].…”