title: The role of the fetal fibroblast and transforming growth factor-beta in a model of human fetal wound repair.
abstract: The fetus heals skin wounds without scar formation. Human fetal skin that is transplanted to a subcutaneous location on an adult athymic mouse and subsequently wounded heals without scar formation, whereas the same fetal skin heals with scar formation when transplanted to a cutaneous location. To characterize the healing process of human fetal skin in these two locations, species-specific human and mouse DNA probes were constructed and used to probe graft wounds under high stringency in situ hybridization conditions. Immunostaining for species-specific fibroblasts, macrophages, and neutrophils was also performed. The cutaneous human fetal graft healed with scar and showed an influx of adult mouse fibroblasts and macrophages. In contrast, subcutaneous human fetal grafts showed exclusively human fetal fibroblasts in the wound environment, an absence of inflammatory cells, and scar-free repair. Thus, the highly organized collagen deposition in scarless human fetal wound repair appears to be intrinsic to the human fetal fibroblast and occurs in the absence of an adult-like inflammatory response. One important cytokine involved in wound repair is transforming growth factor-beta (TGF beta). TGF beta promotes inflammatory cell recruitment and collagen deposition in healing wounds. To determine the role of TGF beta 1 in fetal wound healing, in situ hybridization for TGF beta 1 mRNA expression, immunostaining for TGF beta protein, and species-specific immunohistochemistry for fibroblasts, macrophages, and neutrophils were performed in human adult wounds, fetal wounds, and fetal wounds treated with a TGF beta 1 slow release disk. TGF beta 1 RNA expression and TGF beta protein were found in wounded adult skin. Neither TGF beta 1 mRNA upregulation nor TGF beta protein was detected in human fetal skin after wounding. However, when exogenous TGF beta 1 was added to human fetal skin, induction of TGF beta 1 mRNA expression in human fetal fibroblasts occurred, an adult-like inflammatory response was detected, and the skin healed with scar formation. Thus, non-scarring fetal skin is relatively TGF beta 1 deficient when compared to scarring adult skin. Furthermore, when exogenous TGF beta is added to fetal skin, scarring occurs. TGF beta appears to be an important modulator in scar formation. With a more thorough understanding of scarless repair mechanisms, clinical induction of scarless healing in adults and children soon may be possible.
authors.affiliation: Department of Surgery, Children's Hospital of Philadelphia, PA 19104, USA.
authors.forename: R Y
authors.initials: RY
authors.lastname: Lin
authors.forename: N S
authors.initials: NS
authors.lastname: Adzick
mesh_terms: D000328:Adult; D000818:Animals; D016207:Cytokines / Q000502:physiology; D005333:Fetus / Q000601:surgery*; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta