Integrin-linked kinase regulates the niche of quiescent epidermal stem cells

Abstract

Stem cells reside in specialized niches that are critical for their function. Quiescent hair follicle stem cells (HFSCs) are confined within the bulge niche, but how the molecular composition of the niche regulates stem cell behaviour is poorly understood. Here we show that integrin-linked kinase (ILK) is a key regulator of the bulge extracellular matrix microenvironment, thereby governing the activation and maintenance of HFSCs. ILK mediates deposition of inverse laminin (LN)-332 and LN-511 gradients within the basement membrane (BM) wrapping the hair follicles. The precise BM composition tunes activities of Wnt and transforming growth factor-β pathways and subsequently regulates HFSC activation. Notably, reconstituting an optimal LN microenvironment restores the altered signalling in ILK-deficient cells. Aberrant stem cell activation in ILK-deficient epidermis leads to increased replicative stress, predisposing the tissue to carcinogenesis. Overall, our findings uncover a critical role for the BM niche in regulating stem cell activation and thereby skin homeostasis.

Multi‐tasking epidermal stem cells: Beyond epidermal maintenance

“…Another possible role for stem cell quiescence is to regulate tissue architecture. Some of the mutant mice that lost hair follicle stem cell quiescence exhibit bulge structural changes (Baker et al, 2010;Fujiwara et al, 2011;Kobielak et al, 2007;Morgner et al, 2015), suggesting the role of bulge quiescence in controlling global epidermal/organ tissue architecture. Indeed, in the epithelia, local modulation of cell proliferation rate influences the shape of the epithelia (Varner & Nelson, 2014).…”

Rejuvenating Strategies for Stem Cell-Based Therapies in Aging

“…These signals may influence SC function directly or through modulation of the local environment. Indirect action includes changes to the makeup of the resident immune cell population, modulation of stromal or somatic cell function, and perturbation of the secretory phenotype of these cells (Jones and Wagers, 2008; Li et al, 2016a; Morgner et al, 2015; Rezza et al, 2016; Scadden, 2014; Wagers, 2012). …”

Gata6 promotes hair follicle progenitor cell renewal by genome maintenance during proliferation

“…This depends on full replication‐origin licensing via MCM3 (Alvarez et al , ). In the hair follicle, a mutation that promotes proliferation of otherwise quiescent hair follicle stem cells (HFSCs) also leads to increased DNA damage and premature aging (Morgner et al , ).…”