Differential Activation of Migration by Hypoxia in Keratinocytes Isolated from Donors of Increasing Age: Implication for Chronic Wounds in the Elderly

Abstract

Chronic wound healing conditions are often observed in elderly patients with poor tissue oxygenation. Impaired re-epithelialization is a hallmark of these wounds, which is seen in both clinical studies and in our animal models of impaired healing. To investigate the pathogenic mechanism of chronic wounds, we studied the effect of hypoxia on migration of keratinocytes isolated 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 changes demonstrated a differential activation of matrix metalloproteinases by hypoxia in keratinocytes isolated from the young and the old. Matrix metalloproteinases-1 and -9 and tissue inhibitor of matrix metalloproteinase-1 were strongly upregulated by hypoxia in young cells, whereas no induction was observed in aged cells. Furthermore, transforming growth factor-beta 1 signaling appears to be involved in the keratinocyte differential response to hypoxia, as transforming growth factor-beta type I receptor was upregulated by hypoxia in young cells, while there was no induction in aged cells. Transforming growth factor-beta neutralizing reagents blocked hypoxia-induced matrix metalloproteinase-1, matrix metalloproteinase-9 expression, and hypoxia-induced cell migration as well. Our results suggest that an age-related decrease in response to hypoxia plays a crucial part in the pathogenesis of retarded re-epithelialization in wound.

Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90α autocrine signaling to promote keratinocyte migration

“…Hypoxia promotes migration of human keratinocytes (HKs) (O'Toole et al, 1997;Xia et al, 2001) and dermal fibroblasts (Mogford et al, 2002;Lerman et al, 2003;Li et al, 2007). Acute hypoxia is probably a driving force during skin wound healing (Tandara and Mustoe, 2004).…”

Oxygen in wound healing: More than a nutrient

“…The expression of TGF-beta receptors in human keratinocytes showed the same pattern as fibroblasts [23].…”

“…Aged human keratinocytes show decreased motility in response to hypoxiakeratinocytes in comparison to young adult [23]. Aged human fibroblasts show a decrease in migration when stimulated by TGF-␤.…”

“…Hypoxic conditions enhance cell migration of skin-derived cells: Keratinocytes move faster under hypoxia [23,28]. Also, human dermal fibroblasts have increased motility under short-term hypoxia [22].…”

A pilot study evaluating protein abundance in pressure ulcer fluid from people with and without spinal cord injury

“…Elevated MMPs in chronic wounds have been reported, 25 but comparisons of MMP concentrations from pressure ulcer wound fluid of people with and without SCI have not been previously reported. Xia et al 53 reported that tissue from aged donors had a higher basal level of MMP expression compared to younger donors. Therefore, it is possible that the differences we observed between the subjects with SCI and the elderly subjects without SCI in the present study are age-related.…”