Effect of age and hypoxia on TGFβ1 receptor expression and signal transduction in human dermal fibroblasts: Impact on cell migration

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Abstract
Wound healing is critically affected by age, ischemia, and growth factors such as TGFβ1. The combined effect of these factors on fibroblast migration, an essential component of wound healing, is poorly understood. To address this deficiency, we examined expression of TGFβ receptor type I and II (TGFβRI and RII) under normoxia or hypoxia (1% O2) in cultured human dermal fibroblasts (HDFs) from young (ages 24–33) and aged (ages 61–73) adults. TGFβRI and RII expression was similar in both groups under normoxia. Hypoxia did not alter receptor levels in young HDFs but significantly decreased TGFβRI in aged cells (12 and 43%, respectively). Additionally, young cells displayed a 50% increase in activation of p42/p44 mitogen-activated kinase by TGFβ1 (2–200 pg/ml) under hypoxia while aged cell levels of active p42/p44 decreased up to 24%. To determine functional outcomes of these findings, we measured the migratory capacity of the cells on type I collagen using a gold salt migration assay. Hypoxia increased the migratory index (MI) of young HDFs over normoxia by 30% but had no effect on aged cells. Under normoxia, TGFβ1 (1–1000 pg/ml) increased young HDF migration in a concentration-dependent manner up to 109% over controls but minimally increased aged HDF migration (37%). Under hypoxia, TGFβ1 significantly increased young cell MI at all concentrations but was without effect on the aged HDF response. These data demonstrate that aged fibroblasts have an impaired migratory capacity with complete loss of responsiveness to hypoxia and deficits in the migratory and signal transduction responsiveness to TGFβ1 that may partly explain diminished healing capabilities often observed in aged patients. J. Cell. Physiol. 190: 259–265, 2002.