Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3.
In the first-trimester mammalian fetus, skin wounds heal with perfect reconstitution of the dermal architecture without scar formation. Understanding environmental molecular regulation in fetal wound healing may reveal scar-limiting therapeutical strategies for the prevention of postnatal scarring wound repair. Therefore, we performed studies on fetal skin oxygenation and skin and wound expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in the sheep model in vivo and performed studies on the potential relevance of HIF-1alpha during wound healing in vitro. Skin oxygen partial pressure levels were hypoxic throughout normal development. In nonscarring fetal skin at gestation day (GD)60, HIF-1alpha could be detected neither in healthy nor in wounded tissue. At GD100, in wounds with minimal scar formation, HIF-1alpha was expressed in fibroblasts and was markedly up-regulated at the wound edge. In scarring fetal wounds at GD120, HIF-1alpha was predominantly expressed in inflammatory cells. Expression of transforming growth factor beta3 (TGF-beta3), a potent antiscarring cytokine, overlapped with HIF-1a expression at GD100. HIF-1alpha-deficient mouse embryonic fibroblasts showed impaired migratory capabilities and demonstrated that TGF-beta3, but not proscarring TGF-beta1, manifests hypoxia- and HIF-1alpha-dependent regulation. In conclusion, HIF-1alpha-dependent regulation of a potent antiscarring cytokine may provide new strategies for antiscarring manipulation of wound healing.
Scheid
Annette
A
Department of Surgery, University Children's Hospital of Zürich, Switzerland. ascheid@physiol.unizh.ch
Wenger
Roland H
RH
Schäffer
Leonhard
L
Camenisch
Isabelle
I
Distler
Oliver
O
Ferenc
Andrej
A
Cristina
Heidi
H
Ryan
Heather E
HE
Johnson
Randall S
RS
Wagner
Klaus F
KF
Stauffer
Urs G
UG
Bauer
Christian
C
Gassmann
Max
M
Meuli
Martin
M
D000818:Animals; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D005333:Fetus / Q000033:anatomy & histology / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012756:Sheep; D012867:Skin / Q000196:embryology* / Q000378:metabolism; D012871:Skin Diseases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D053782:Transforming Growth Factor beta3; D014945:Wound Healing
D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C509045:Tgfb3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3