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Free keywords:
Animals
Basement Membrane
Blotting, Western
Carcinogens/pharmacology
Cell Adhesion
Cell Adhesion Molecules/metabolism
Cell Proliferation
Electrophoresis, Polyacrylamide Gel
Epidermis/cytology
Extracellular Matrix/*genetics/metabolism
Flow Cytometry
Fluorescent Antibody Technique
Gene Knockout Techniques
Hair Follicle/*cytology
Immunohistochemistry
Keratinocytes/*metabolism
Laminin/metabolism
Mice
Protein-Serine-Threonine Kinases/*genetics/metabolism
Real-Time Polymerase Chain Reaction
Sequence Analysis, RNA
Skin/drug effects
Stem Cell Niche/*genetics
Stem Cells/cytology/*metabolism
Tetradecanoylphorbol Acetate/pharmacology
Transforming Growth Factor beta
Wnt Signaling Pathway
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-beta 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.
