Differential activation of migration by hypoxia in keratinocytes isolated from donors of increasing age: Implication for chronic wounds in the elderly

Chronic wound healing conditions are often observed in elderly patients wit h poor tissue oxygenation. Impaired re-epithelialization is a hallmark of t hese wounds, which is seen in both clinical studies and in our animal model s of impaired healing. To investigate the pathogenic mechanism of chronic w ounds, we studied the effect of hypoxia on migration of keratinocytes isola ted from human donors of increasing age. Keratinocytes from elderly donors had depressed migratory activity when exposed to hypoxia, as opposed to an increase in migration in young cells. Analysis of underlying biochemical ch anges demonstrated a differential activation of matrix metalloproteinases b y hypoxia in keratinocytes isolated from the young and the old. Matrix meta lloproteinases-1 and -9 and tissue inhibitor of matrix metalloproteinase-1 were strongly upregulated by hypoxia in young cells, whereas no induction w as observed in aged cells. Furthermore, transforming growth factor-beta1 si gnaling appears to be involved in the keratinocyte differential response to hypoxia, as transforming growth factor-beta type I receptor was upregulate d by hypoxia in young cells, while there was no induction in aged cells. Tr ansforming growth factor-beta neutralizing reagents blocked hypoxia-induced matrix metalloproteinase-1, matrix metalloproteinase-9 expression, and hyp oxia-induced cell migration as well. Our results suggest that an age-relate d decrease in response to hypoxia plays a crucial part in the pathogenesis of retarded re-epithelialization in wound.