Abstract
BackgroundThere is a major discrepancy between the in vitro and in vivo results regarding the role of β1 integrins in the maintenance of epidermal stem/progenitor cells. Studies of mice with skin-specific ablation of β1 integrins suggested that epidermis can form and be maintained in their absence, while in vitro data have shown a fundamental role for these adhesion receptors in stem/progenitor cell expansion and differentiation.Methodology/Principal FindingsTo elucidate this discrepancy we generated hypomorphic mice expressing reduced β1 integrin levels on keratinocytes that developed similar, but less severe defects than mice with β1-deficient keratinocytes. Surprisingly we found that upon aging these abnormalities attenuated due to a rapid expansion of cells, which escaped or compensated for the down-regulation of β1 integrin expression. A similar phenomenon was observed in aged mice with a complete, skin-specific ablation of the β1 integrin gene, where cells that escaped Cre-mediated recombination repopulated the mutant skin in a very short time period. The expansion of β1 integrin expressing keratinocytes was even further accelerated in situations of increased keratinocyte proliferation such as wound healing.Conclusions/SignificanceThese data demonstrate that expression of β1 integrins is critically important for the expansion of epidermal progenitor cells to maintain epidermal homeostasis.
Highlights
Integrins are heterodimeric cell surface receptors consisting of one a and one b subunit
The hypomorphic gene mutation was obtained by introducing a 141-bp long wildtype cDNA fragment of the b1 integrin gene coding for the entire b1 integrin cytoplasmic tail, including the stop codon from exon 16, in frame into exon 15
The hpmKIneo-tk+ mutation was transferred into embryonic stem (ES) cells by homologous recombination, and the neo-tk selection cassette was subsequently removed by transient expression of Cre recombinase leaving one loxP site in the non coding region
Summary
Integrins are heterodimeric cell surface receptors consisting of one a and one b subunit. In order to clarify the discrepancy between the in vitro and in vivo results on the role of b1 integrin in the maintenance of epidermal stem cells we generated a mouse strain with reduced b1 integrin expression in keratinocytes of the skin This approach allows to study the function of b1 integrin in skin homeostasis avoiding the gross abnormalities seen in mice with skin specific ablation of b1 integrin. Using this new model we could show that keratinocytes that express normal levels of b1 integrin due to inefficient downregulation of b1 integrin expression are able to quickly expand in the interfollicular epidermis and almost completely replace the mutant cells over time. This rapid expansion of cells ensures nearly normal epidermal homeostasis and strongly indicates that b1 integrins play a very critical role for the proliferation and maintenance of EPC in vivo
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