Keratinocyte Growth Factor Stimulates Migration and Hyaluronan Synthesis in the Epidermis by Activation of Keratinocyte Hyaluronan Synthases 2 and 3

Keratinocyte growth factor (KGF) activates keratinocyte migration and stimulates wound healing. Hyaluronan, an extracellular matrix glycosaminoglycan that accumulates in wounded epidermis, is known to promote cell migration, suggesting that increased synthesis of hyaluronan might be associated with the KGF response in keratinocytes. Treatment of monolayer cultures of rat epidermal keratinocytes led to an elongated and lifted cell shape, increased filopodial protrusions, enhanced cell migration, of hyaluronan in the and and of hyaluronan suggesting cultures of the cell and with the hyaluronan and hyaluronan in the epidermis, the cell in the the of the and epidermal that and to the of KGF in and the that enhanced hyaluronan synthesis an the response of keratinocytes in wound keratinocyte Keratinocyte growth factor (KGF) activates keratinocyte migration and stimulates wound healing. Hyaluronan, an extracellular matrix glycosaminoglycan that accumulates in wounded epidermis, is known to promote cell migration, suggesting that increased synthesis of hyaluronan might be associated with the KGF response in keratinocytes. Treatment of monolayer cultures of rat epidermal keratinocytes led to an elongated and lifted cell shape, increased filopodial protrusions, enhanced cell migration, of hyaluronan in the and and of hyaluronan suggesting cultures of the cell and with the hyaluronan and hyaluronan in the epidermis, the cell in the the of the and epidermal that and to the of KGF in and the that enhanced hyaluronan synthesis an the response of keratinocytes in wound keratinocyte Keratinocyte growth factor growth growth growth factor epidermal growth growth growth factor epidermal of the growth factor is and to the to KGF to of growth factor in the epidermis, is in the the of the keratinocytes in the cell in the cell KGF keratinocyte and migration of KGF is in wounded and KGF the wound suggesting in the wound is glycosaminoglycan in extracellular that the of the matrix that cell migration with with and that hyaluronan synthesis is in keratinocytes to with and of hyaluronan keratinocytes enhanced migration, an of keratinocyte migration suggesting that hyaluronan synthesis be of the of keratinocyte the of KGF in keratinocytes to of the to the matrix and to and migration, and of to and growth factor to that and the hyaluronan matrix keratinocytes and in the migration, wound and response of to the of rat epidermal keratinocyte cell and and and in in with and and and and in cultures with and of and to cultures of in with the and with and the to the in the monolayer to in the KGF and to the the and with the and the of KGF of the monolayer cultures in with and in with KGF and of in in with and in with and with in of the extracellular hyaluronan with to the the with of hyaluronan of and to in with and with and and with in an hyaluronan that the and and the with in and in with and and in with and with with in the with and an with and with and with an the to the of the with of the hyaluronan with and the the the hyaluronan of in the the hyaluronan to of the hyaluronan with the the the of the cultures in in the cultures with in and with and of the epidermis, and the of of to the in the cultures of the with to and hyaluronan and with and in in with to with and in in to with in of of an with with the and with and in the with the cultures with and in and of the and and in with the in the the in the with and with an the to the with and with and the of with and of of in the and and and the of KGF and to the and and of the cell and hyaluronan with of and the and with of and the and the cell the hyaluronan and and the of the of the in with and with of in of to in and with of and in of in and of with the in the in and the the of the hyaluronan the and hyaluronan with cultures of with KGF and and epidermis, and the with of and of the with in and the to the and the with with and with hyaluronan and in to the the with and with and with with and and in with of and the and in of of and cell to of and with with of in with of of in the of the of of the to be in the in the of with the of and the in the of of hyaluronan in the the of known hyaluronan the monolayer cultures with KGF and the and the cultures with the to the with with and to the with the the and in and the and in the in KGF the and and cultures with with and with in with an and with to the of the and and the monolayer with and the with the of the in in of growth factor and an and the cultures with and to the of the epidermis, and the the the the of in the of the and in the migration, and and the the the of and an keratinocyte cell with and be of cultures with KGF with an elongated and of the cell of the an in in in cultures of KGF of migration the wound to the the cell in cultures cell suggesting that migration is KGF in of KGF migration, and hyaluronan in monolayer cultures and hyaluronan of of of in with the of cultures with in and the growth and increased in the of KGF in and with the the enhanced of hyaluronan in the associated with in in of with KGF that the of of the the of hyaluronan in the of and hyaluronan synthesis in monolayer cultures with cultures with KGF and hyaluronan the of and with the and and of and and and with and in the of KGF in the the the hyaluronan in the cell and of cultures and of the in the of the hyaluronan in the and of and of cultures with KGF that in the monolayer cultures of increased the of and the of of the and of and of KGF in the in that to of and that of the of and increased of hyaluronan synthesis of the of KGF in keratinocytes of the hyaluronan the of hyaluronan the of the hyaluronan in the the hyaluronan in the and the cell the the hyaluronan the of of of the hyaluronan of hyaluronan in the of monolayer and cell cultures with and KGF an of with in to of the and the of the the growth KGF increased hyaluronan in the the the KGF the of cell of hyaluronan in cultures in the and the and increased and of in the of hyaluronan in the cell and and in the and with hyaluronan cell hyaluronan to the of the of hyaluronan in the to in the in that the hyaluronan in hyaluronan that KGF associated with the the of the the of the cell and the in the with and the of hyaluronan that and cell that the of the the hyaluronan the in the and the in to the of the to an in the cultures with and with of cell hyaluronan that KGF stimulates hyaluronan the cell of the response in hyaluronan of the that the of hyaluronan KGF the hyaluronan of hyaluronan an KGF is of hyaluronan of the the that the increased hyaluronan an response to the KGF the of in the the that the hyaluronan to the extracellular the in the of KGF and the of and the with the in cultures of is in the epidermis, the to the and to the KGF in the of hyaluronan in the epidermis, and in that the matrix the of KGF hyaluronan synthesis in the that the of hyaluronan of KGF epidermal of hyaluronan and of and the of hyaluronan and in cultures and cultures in and in the of KGF in and and and and and the hyaluronan that the and and that the with the and in to with and and with and cultures with of and to that of increased in cultures with KGF in and and and in of cultures of the hyaluronan in the cell in the cell and the hyaluronan in KGF in with the synthesis of hyaluronan and increased in the and cell and the an increased of of and the cultures the of KGF with the with and and of KGF and the of the suggesting that of cell in the cultures in with the of in cell in monolayer cultures increased of the and increased of the in the of KGF of KGF the and epidermal in cultures of the of in and cultures the the cell of in in the of the epidermal in the of the and and of the suggesting that KGF the of the cultures the epidermal in epidermal to in the cultures of KGF the of in cultures in the and and of KGF and is in and and in and and cultures and the of the and of and and cultures that KGF hyaluronan synthesis in and that the increased hyaluronan synthesis is associated with an increased of the hyaluronan and of hyaluronan synthesis KGF in monolayer cultures and and in lifted and and that the of hyaluronan synthesis the of that hyaluronan synthesis is an of the of is the and of the of KGF of the of KGF is to wound healing. of KGF is and in wounded and the of KGF is associated with enhanced wound the in wound that KGF keratinocyte migration, to of the in an in in with keratinocytes enhanced response with increased hyaluronan suggesting that hyaluronan an in the of keratinocytes. hyaluronan synthesis and migration in keratinocytes with keratinocytes of keratinocyte migration with in cell the of hyaluronan synthesis the cell in keratinocytes is that hyaluronan is an of the and KGF of of KGF in the cultures the of the is in with the that the of the is in the cell the the cell be to the of the hyaluronan in the with the of hyaluronan in the cell cultures of an of the and the to in keratinocyte cultures the of the the of hyaluronan in the cell and the of epidermal with and of hyaluronan synthesis and that of hyaluronan synthesis and and the of epidermal and the synthesis of hyaluronan in the that hyaluronan keratinocyte an that that the of hyaluronan KGF in the and is in to the hyaluronan that KGF and to hyaluronan is to the and associated with cell synthesis is the the cell hyaluronan is in the of the hyaluronan in the be to the and in the the cell with the with hyaluronan and the of the hyaluronan the migration, to the in the increased hyaluronan in the an enhanced hyaluronan accumulates in and hyaluronan synthesis KGF in the monolayer and in the of the in the the cultures and in the epidermal keratinocytes that and to growth and and growth factor that the of of the of the the that growth factor in and an of and the synthesis and of hyaluronan in the increased of and the of hyaluronan in the of keratinocytes and in the to epidermal Keratinocyte growth factor growth growth growth factor epidermal growth growth growth factor epidermal of the growth factor is and to the to KGF to of growth factor in the epidermis, is in the the of the keratinocytes in the cell in the cell KGF keratinocyte and migration of KGF is in wounded and KGF the wound suggesting in the wound keratinocyte growth factor epidermal growth factor keratinocyte growth factor rat epidermal keratinocyte keratinocyte growth factor epidermal growth factor keratinocyte growth factor rat epidermal keratinocyte is glycosaminoglycan in extracellular that the of the matrix that cell migration with with and that hyaluronan synthesis is in keratinocytes to with and of hyaluronan keratinocytes enhanced migration, an of keratinocyte migration suggesting that hyaluronan synthesis be of the of keratinocyte the of KGF in keratinocytes to of the to the matrix and to and migration, and of to and growth factor to that and the hyaluronan matrix keratinocytes and in the migration, wound and response of to the of rat epidermal keratinocyte cell and and and in in with and and and and in cultures with and of and to cultures of in with the and with and the to the in the monolayer to in the KGF and to the the and with the and the of KGF of the monolayer cultures in with and in with KGF and of in in with and in with and with in of the extracellular hyaluronan with to the the with of hyaluronan of and to in with and with and and with in an hyaluronan that the and and the with in and in with and and in with and with with in the with and an with and with and with an the to the of the with of the hyaluronan with and the the the hyaluronan of in the the hyaluronan to of the hyaluronan with the the the of the cultures in in the cultures with in and with and of the epidermis, and the of of to the in the cultures of the with to and hyaluronan and with and in in with to with and in in to with in of of an with with the and with and in the with the cultures with and in and of the and and in with the in the the in the with and with an the to the with and with and the of with and of of in the and and and the of KGF and to the and and of the cell and hyaluronan with of and the and with of and the and the cell the hyaluronan and and the of the of the in with and with of in of to in and with of and in of in and of with the in the in and the the of the hyaluronan the and hyaluronan with cultures of with KGF and and epidermis, and the with of and of the with in and the to the and the with with and with hyaluronan and in to the the with and with and with with and and in with of and the and in of of and cell to of and with with of in with of of in the of the of of the to be in the in the of with the of and the in the of of hyaluronan in the the of known hyaluronan the monolayer cultures with KGF and the and the cultures with the to the with with and to the with the the and in and the and in the in KGF the and and cultures with with and with in with an and with to the of the and and the monolayer with and the with the of the in in of growth factor and an and the cultures with and to the of the epidermis, and the the the the of in the of the and in the migration, and and the the rat epidermal keratinocyte cell and and and in in with and and and and in cultures with and of and to cultures of in with the and with and the to the KGF in the monolayer to in the KGF and to the the and with the and the of KGF of the monolayer cultures in with and in with KGF and of in in with and in with and with in of the extracellular hyaluronan with to the the with of hyaluronan of and to in with and with and and with in an hyaluronan that the and and the with in and in with and and in with and with with in the with and an with and with and with an the to the of the with of the hyaluronan with and the the the hyaluronan of in the the hyaluronan to of the hyaluronan with the the the of the cultures in in the cultures with in and with and of the epidermis, and the of of to the in the cultures of the with to and hyaluronan and with and in in with to with and in in to with in of of an with with the and with and in the with the cultures with and in and of the and and in with the in the the in the with and with an the to the with and with and the of with and of of in the and and and the of KGF and to the and and of the cell and hyaluronan with of and the and with of and the and the cell the hyaluronan and and the of the of the in with and with of in of to in and with of and in of in and of with the in the in and the the of the hyaluronan the and hyaluronan with cultures of with KGF and and epidermis, and the with of and of the with in and the to the and the with with and with hyaluronan and in to the the with and with and with with and and in with of and the and in of of and cell to of and with with of in with of of in the of the of of the to be in the in the of with the of and the in the of of hyaluronan in the the of known hyaluronan the monolayer cultures with KGF and the and the cultures with the to the with with and to the with the the and in and the KGF the and and cultures with with and with in with an and with to the of the and and the monolayer with and the with the of the in in of growth factor and an and the cultures with and to the of the epidermis, and the the the the of in the of the and in the migration, and and the the the of and an keratinocyte cell with and be of cultures with KGF with an elongated and of the cell of the an in in in cultures of KGF of migration the wound to the the cell in cultures cell suggesting that migration is KGF in of KGF migration, and hyaluronan in monolayer cultures and hyaluronan of of of in with the of cultures with in and the growth and increased in the of KGF in and with the the enhanced of hyaluronan in the associated with in in of with KGF that the of of the the of hyaluronan in the and of cultures with KGF that in the monolayer cultures of increased the of and the of of the and of and of KGF in the in that to of and that of the of and increased of hyaluronan synthesis of the of KGF in keratinocytes of the hyaluronan the of hyaluronan the of the hyaluronan in the the hyaluronan in the and the cell the the hyaluronan the of of of the hyaluronan of hyaluronan in the of monolayer and cell cultures with and KGF an of with in to of the and the of the the growth KGF increased hyaluronan in the the the KGF the of cell of hyaluronan in cultures in the and the and increased and of in the of hyaluronan in the cell and and in the and with hyaluronan cell hyaluronan to the of the of hyaluronan in the to in the in that the hyaluronan in hyaluronan that KGF associated with the the of the the of the cell and the in the with and the of hyaluronan that and cell that the of the the hyaluronan the in the and the in to the of the to an in the cultures with and with of cell hyaluronan that KGF stimulates hyaluronan the cell of the response in hyaluronan of the that the of hyaluronan KGF the hyaluronan of hyaluronan an KGF is of hyaluronan of the the that the increased hyaluronan an response to the KGF the of in the the that the hyaluronan to the extracellular the in the of KGF and the of and the with the in cultures of is in the epidermis, the to the and to the KGF in the of hyaluronan in the epidermis, and in that the matrix the of KGF hyaluronan synthesis in the that the of hyaluronan of KGF epidermal of hyaluronan and of and the of hyaluronan and in cultures and cultures in and in the of KGF in and and and and and the hyaluronan that the and and that the with the and in to with and and with and cultures with of and to that of increased in cultures with KGF in and and and in of cultures of the hyaluronan in the cell in the cell and the hyaluronan in KGF in with the synthesis of hyaluronan and increased in the and cell and the an increased of of and the cultures the of KGF with the with and and of KGF and the of the suggesting that of cell in the cultures in with the of in cell in monolayer cultures increased of the and increased of the in the of KGF of KGF the and epidermal in cultures of the of in and cultures the the cell of in in the of the epidermal in the of the and and of the suggesting that KGF the of the cultures the epidermal in epidermal to in the cultures of KGF the of in cultures in the and and of KGF and is in and and in and and cultures and the of the and of and and cultures KGF the of and an keratinocyte cell with and be of cultures with KGF with an elongated and of the cell of the an in in in cultures of KGF of migration the wound to the the cell in cultures cell suggesting that migration is KGF in and the growth and increased in the of KGF in and with the the enhanced of hyaluronan in the associated with in in of with KGF that the of of the the of hyaluronan in the and of cultures with KGF that in the monolayer cultures of increased the of and the of of the and of and of KGF in the in that to of and that of the of and increased of hyaluronan synthesis of the of KGF in keratinocytes of the hyaluronan KGF the of hyaluronan the of the hyaluronan in the the hyaluronan in the and the cell the the hyaluronan the of of of the hyaluronan the growth KGF increased hyaluronan in the the the KGF the of cell of hyaluronan in cultures in the and the and increased and of in the of hyaluronan in the cell and and in the and with hyaluronan cell hyaluronan to the of the of hyaluronan in the to in the in that the hyaluronan in hyaluronan that KGF associated with the the of the the of the cell and the in the with and the of hyaluronan that and cell that the of the the hyaluronan the in the and the in to the of the to an in the cultures with and with of cell hyaluronan that KGF stimulates hyaluronan the cell of the response in hyaluronan of the that the of hyaluronan KGF the hyaluronan of hyaluronan an KGF is of hyaluronan of the the that the increased hyaluronan an response to the KGF the of in the the that the hyaluronan to the extracellular the in the of KGF and the of and the with the in cultures of is in the epidermis, the to the and to the KGF in the of hyaluronan in the epidermis, and in that the matrix the of KGF hyaluronan synthesis in the that the of hyaluronan of the hyaluronan in the cell in the cell and the hyaluronan in KGF in with the synthesis of hyaluronan and increased in the and cell and the an increased of of and the cultures the of KGF with the with and and of KGF and the of the suggesting that of cell in the cultures in with the of in cell in monolayer cultures increased of the and increased of the in the of KGF in the of the epidermal in the of the and and of the suggesting that KGF the of the cultures the epidermal in epidermal to in the cultures that KGF hyaluronan synthesis in and that the increased hyaluronan synthesis is associated with an increased of the hyaluronan and of hyaluronan synthesis KGF in monolayer cultures and and in lifted and and that the of hyaluronan synthesis the of that hyaluronan synthesis is an of the of is the and of the of KGF of the of KGF is to wound healing. of KGF is and in wounded and the of KGF is associated with enhanced wound the in wound that KGF keratinocyte migration, to of the in an in in with keratinocytes enhanced response with increased hyaluronan suggesting that hyaluronan an in the of keratinocytes. hyaluronan synthesis and migration in keratinocytes with keratinocytes of keratinocyte migration with in cell the of hyaluronan synthesis the cell in keratinocytes is that hyaluronan is an of the and KGF of of KGF in the cultures the of the is in with the that the of the is in the cell the the cell be to the of the hyaluronan in the with the of hyaluronan in the cell cultures of an of the and the to in keratinocyte cultures the of the the of hyaluronan in the cell and the of epidermal with and of hyaluronan synthesis and that of hyaluronan synthesis and and the of epidermal and the synthesis of hyaluronan in the that hyaluronan keratinocyte an that that the of hyaluronan KGF in the and is in to the hyaluronan that KGF and to hyaluronan is to the and associated with cell synthesis is the the cell hyaluronan is in the of the hyaluronan in the be to the and in the the cell with the with hyaluronan and the of the hyaluronan the migration, to the in the increased hyaluronan in the an enhanced hyaluronan accumulates in and hyaluronan synthesis KGF in the monolayer and in the of the in the the cultures and in the epidermal keratinocytes that and to growth and and growth factor that the of of the of the the that growth factor in and an of and the synthesis and of hyaluronan in the increased of and the of hyaluronan in the of keratinocytes and in the to epidermal that KGF hyaluronan synthesis in and that the increased hyaluronan synthesis is associated with an increased of the hyaluronan and of hyaluronan synthesis KGF in monolayer cultures and and in lifted and and that the of hyaluronan synthesis the of that hyaluronan synthesis is an of the of is the and of the of KGF of the of KGF is to wound healing. of KGF is and in wounded and the of KGF is associated with enhanced wound the in wound that KGF keratinocyte migration, to of the in an in in with keratinocytes enhanced response with increased hyaluronan suggesting that hyaluronan an in the of keratinocytes. hyaluronan synthesis and migration in keratinocytes with keratinocytes of keratinocyte migration with in cell the of hyaluronan synthesis the cell in keratinocytes is that hyaluronan is an of the and KGF of of KGF in the cultures the of the is in with the that the of the is in the cell the the cell be to the of the hyaluronan in the with the of hyaluronan in the cell cultures of an of the and the to in keratinocyte cultures the of the the of hyaluronan in the cell and the of epidermal with and of hyaluronan synthesis and that of hyaluronan synthesis and and the of epidermal and the synthesis of hyaluronan in the that hyaluronan keratinocyte an that that the of hyaluronan KGF in the and is in to the hyaluronan that KGF and to hyaluronan is to the and associated with cell synthesis is the the cell hyaluronan is in the of the hyaluronan in the be to the and in the the cell with the with hyaluronan and the of the hyaluronan the migration, to the in the increased hyaluronan in the an enhanced hyaluronan accumulates in and hyaluronan synthesis KGF in the monolayer and in the of the in the the cultures and in the epidermal keratinocytes that and to growth and and growth factor that the of of the of the the that growth factor in and an of and the synthesis and of hyaluronan in the increased of and the of hyaluronan in the of keratinocytes and in the to epidermal and the to the of the of of and the of the