Recent clinical and experimental evidence suggests that the fetus responds to surgical injury in a fashion fundamentally different from the adult: the fetus heals rapidly without the scarring and inflammation that accompany adult wounds. The mechanisms that underlie these differences are unknown. We have established scarless repair models in both the long-gestation fetal sheep model and in an adult athymic mouse model of human fetal skin repair. We determined that scarless fetal repair appears to be intrinsic to fetal tissue and is not secondary to extrinsic fetal environmental factors (e.g., amniotic fluid exposure). We hypothesize that scarless fetal repair is a consequence of a unique extracellular matrix (ECM) produced by the fetal fibroblast in conjunction with the absence of an adult-like inflammatory response to injury. Our general strategy is to delineate the crucial ECM (collagen and proteoglycan) and cellular (fibroblast, myofibroblast, inflammatory cell) components that differentiate fetal from adult healing using these established fetal repair models.
The first aim of this proposal is to use established morphologic techniques to investigate the ECM (proteoglycan) and cellular (myofibroblast, inflammatory cell) components that distinguish fetal from adult repair in sheep, particularly during the in utero transition from scarless fetal wound healing to """"""""adult"""""""" healing with scar formation. Related studies will determine the relative contributions of fetal/adult ECM and fetal/adult cells at the healing interface of adult sheep skin transplanted onto fetal lambs, since scarring occurs only within the adult skin at this adult-fetal tissue interface. The second objective is to define the biochemical (collagen types, glycosaminoglycan profile) and biomechanical (wound breaking strength) differences between fetal and adult sheep wound repair.
The third aim i s to characterize a unique model of scarless human fetal skin healing using human fetal skin grafts that are wounded after transplantation onto adult athymic mice. Experiments are planned to elucidate the role of species-specific ECM, adult mouse vs. fetal human fibroblasts, inflammatory cells, growth factor profile, differentiation, and the air-tissue interface in this model of scarless human fetal wound healing. Our long-term objective is to apply this knowledge clinically to avoid scarring (keloids, intra-peritoneal adhesions, strictures, etc.) by altering the ECM and cellular response of adult wounds so that healing occurs in a more fetal-like manner.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD025505-04A1
Application #
3326648
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1989-12-01
Project End
1997-02-28
Budget Start
1993-03-18
Budget End
1994-02-28
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Lovvorn 3rd, H N; Cheung, D T; Nimni, M E et al. (1999) Relative distribution and crosslinking of collagen distinguish fetal from adult sheep wound repair. J Pediatr Surg 34:218-23
Quinn, T M; Sylvester, K G; Kitano, Y et al. (1999) TGF-beta2 is increased after fetal tracheal occlusion. J Pediatr Surg 34:701-4;discussion 704-5
Stelnicki, E J; Komuves, L G; Kwong, A O et al. (1998) HOX homeobox genes exhibit spatial and temporal changes in expression during human skin development. J Invest Dermatol 110:110-5
Cass, D L; Quinn, T M; Yang, E Y et al. (1998) Increased cell proliferation and decreased apoptosis characterize congenital cystic adenomatoid malformation of the lung. J Pediatr Surg 33:1043-6;discussion 1047
Cass, D L; Bullard, K M; Sylvester, K G et al. (1998) Epidermal integrin expression is upregulated rapidly in human fetal wound repair. J Pediatr Surg 33:312-6
Lovvorn 3rd, H N; Cass, D L; Sylvester, K G et al. (1998) Hyaluronan receptor expression increases in fetal excisional skin wounds and correlates with fibroplasia. J Pediatr Surg 33:1062-9;discussion 1069-70
Meuli-Simmen, C; Meuli, M; Yingling, C D et al. (1997) Midgestational sciatic nerve transection in fetal sheep results in absent nerve regeneration and neurogenic muscle atrophy. Plast Reconstr Surg 99:486-92
Bullard, K M; Cass, D L; Banda, M J et al. (1997) Transforming growth factor beta-1 decreases interstitial collagenase in healing human fetal skin. J Pediatr Surg 32:1023-7
Cass, D L; Bullard, K M; Sylvester, K G et al. (1997) Wound size and gestational age modulate scar formation in fetal wound repair. J Pediatr Surg 32:411-5

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