Oxygen deprivation inhibits basal keratinocyte proliferation in a model of human skin and induces regio-specific changes in the distribution of epidermal adherens junction proteins, aquaporin-3, and glycogen.
It is generally accepted that hypoxia and recovery from oxygen deprivation contribute to the breakdown and ulceration of human skin. The effects of these stresses on proliferation, differentiation and expression of cell-cell adhesion molecules were investigated for the first time in an organotypic model of human skin. Fully stratified tissues were exposed to a time course of oxygen deprivation and subsequent reoxygenation. Regional changes in keratinocyte morphology, glycogen stores and cellular junctions were observed, with more differentiated layers of the epidermis exhibiting the first evidence of oxygen deprivation. Cellular swelling within the granular layer was concurrent with aquaporin-3 depletion. The keratinocyte adherens junction proteins E-cadherin and beta-catenin were dramatically decreased in a regio-specific manner throughout the epidermis following oxygen deprivation. In contrast, P-cadherin and the desmosomal proteins desmoplakin and desmoglein-1 were refractory to oxygen deprivation. Relative to normoxic controls, hypoxic tissues exhibited increased mRNA levels of the transcriptional repressor Slug; however, mRNA levels of the related transcriptional factor Snail were unaffected. All cellular and molecular changes were reversible upon reoxygenation. These results show that oxygen deprivation and reoxygenation exert differential effects on epidermal adhesion proteins and suggest a novel role for cadherins, beta-catenin, and Slug in hypoxia-induced junctional changes occurring in stratified squamous epithelium.
Straseski
Joely A
JA
Department of Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706-1102, USA.
Gibson
Angela L
AL
Thomas-Virnig
Christina L
CL
Allen-Hoffmann
B Lynn
BL
D022005:Adherens Junctions / Q000502:physiology*; D000818:Animals; D051400:Aquaporin 3 / Q000378:metabolism*; D049109:Cell Proliferation; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D015603:Keratinocytes / Q000502:physiology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D014945:Wound Healing / Q000502:physiology
D051400:Aquaporin 3; D006003:Glycogen