Prostaglandin E2 differentially regulates contraction and structural reorganization of anchored collagen gels by human adult and fetal dermal fibroblasts

Contraction and remodeling of granulation tissue by fibroblasts is a crucial component of dermal wound healing. Postnatal wounds heal with imperfect repair and scar formation, whereas tissue repair in fetal wounds is regenerative. Prostaglandin E2 (PGE2) modulates the behavior of fibroblasts in the wound bed. This study was designed to investigate the mechanism by which PGE2 regulates an in vitro model of granulation tissue, anchored collagen gels, by human adult and fetal dermal fibroblasts. We hypothesized that PGE2 differentially regulates contraction and remodeling of anchored collagen gels by these fibroblast phenotypes. These results indicate that once tension was generated, fetal fibroblasts exerted lower contractile forces resulting in less collagen contraction. This coincided with less prominent stress fibers, yet fetal fibroblasts were able to substantially remodel the collagen architecture. This mechanism was differentially modulated by PGE2 and was mimicked with a PGE2 receptor agonist, indicating a cyclic adenosine monophosphate (cAMP)-dependent mechanism through the EP2 receptor. However, direct up-regulation of cAMP led to decreases in contraction and remodeling by both fibroblast phenotypes indicating an altered signaling pathway. Therefore, targeting cAMP via the EP2 receptor could potentially decrease adult fibroblast contractile forces to the levels of the fetal fibroblast phenotype in order to decrease dermal scarring.     

Hyaluronic acid degradation products induce neovascularization and fibroplasia in fetal rabbit wounds.

Scarless fetal wound healing occurs with mild fibroplasia and neovascularization, while the wound is persistently enriched with hyaluronic acid. Conversely, adult wounds are characterized by prominent fibroplasia, neovascularization, and scar formation, and hyaluronic acid is a transient component of the early adult wound matrix. Our group has reported that enzymatic degradation of fetal rabbit wound hyaluronic acid results in marked increases in fibroplasia, collagen deposition, and neovascularization. This altered, adultlike healing response is hypothesized to have resulted from the generation of biologically active hyaluronic acid degradation products. Therefore, this study analyzes the fibrovascular inductive activity of hyaluronic acid degradation products. Fetal rabbit wounds were treated with hyaluronic acid degradation products generated by methods known to produce oligosaccharides with significant angiogenic activity. Implants from wounds treated with either of the control solutions (n = 4 for each control) had identical histologic features characterized by a mild mononuclear cell infiltrate but neither infiltrating fibroblasts nor collagen. In marked contrast, implants from wounds treated with hyaluronic acid degradation products contained infiltrating fibroblasts and collagen intermixed with numerous blood vessels. Quantitation of capillary ingrowth showed a sixfold increase in the neovascular response in wounds treated with hyaluronic acid degradation products compared with either controls (p < 0.05). This study shows that hyaluronic acid degradation products stimulate neovascularization and fibroplasia in fetal wounds. These observations suggest that a balance between hyaluronic acid accumulation and degradation has significant regulatory influence in fetal tissue repair.     

Biology of fetal wound healing: collagen biosynthesis during dermal repair.

The rapid restoration of tissue integrity and breaking strength in healing fetal wounds is mainly a function of fetal wound collagen. In this study, the fetal and adult tissue responses to injury were characterized in terms of changes in collagen biosynthesis. Linear wounds and unwounded skin were incubated with radioactive proline, and collagen synthesis was measured as isotope incorporation into collagenase-sensitive protein. Likewise, noncollagen protein synthesis was represented by isotope incorporation into collagenase-resistant protein. Adult wounds demonstrated a preferential stimulation of collagen as compared with noncollagen protein synthesis after wounding. In contrast, both collagen and noncollagen protein synthesis were significantly elevated in the fetus during the first 5 days postwounding. Despite marked increases in fetal wound collagen synthesis above both unwounded fetal skin and adult wound levels, fetal wounds exhibited no evidence of excessive collagen deposition or scar formation after wounding. These findings suggest that the fetal response to tissue injury is a function of the distinctive qualities of fetal fibroblasts associated with the extracellular wound matrix and may involve rapid collagen turnover and degradation.     

The altered mechanical phenotype of fetal fibroblasts hinders myofibroblast differentiation

During the dermal wound healing process, the mechanical rigidity of the newly deposited extracellular matrix and transforming growth factor‐β1 promote the transition of fibroblasts into myofibroblasts. Myofibroblasts generate large cellular forces that contract and remodel the extracellular matrix leading to scar formation. In contrast, myofibroblasts are not detected in fetal dermal wounds which are more compliant and contain less transforming growth factor‐β1 than adult wounds. Instead, fetal fibroblasts orchestrate scarless healing of dermal wounds resulting in healed tissues that resemble uninjured dermis. While these biomechanical differences suggest that the fetal wound environment promotes smaller cellular forces which enable regeneration, previous studies indicate that fetal fibroblasts have unique contractile properties that may facilitate scarless dermal repair. Therefore, we tested whether physiologic wound rigidities and transforming growth factor‐β1 induce contractile forces and myofibroblast differentiation of fetal dermal fibroblasts. In comparison to their adult dermal counterparts, we found that fetal fibroblasts exhibit a deficient contractile response to rigid extracellular matrix and transforming growth factor‐β1. Our data suggest that the contractile phenotype of fetal dermal fibroblasts limits their cellular force production and prevents their ability to differentiate into myofibroblasts.     

Studies in fetal wound healing, VI. Second and early third trimester fetal wounds demonstrate rapid collagen deposition without scar formation

The mechanisms that underlie the lack of scarring in fetal wounds are unknown, but probably relate to the control of collagen fibrillogenesis. The role of collagen in the fetal wound matrix is controversial, and several wound implant models have been used to evaluate collagen deposition in fetal wounds. Unfortunately, these models create an artificial wound environment and may thereby affect the results. In order to study fetal wound collagen deposition in linear wounds without artificially altering the wound environment, we applied a highly sensitive immunohistochemical technique that uses antibodies to collagen types I, III, IV, and VI. We found that collagen was deposited in fetal wounds much more rapidly than in adult wounds. Wound collagen deposition occurred in a normal dermal and mesenchymal pattern in second and early third trimester fetal lambs. These findings are consistent with the observation that the fetus heals rapidly and without scar formation. In contrast, wounds in late gestation fetal lambs showed some evidence of scar formation. Further studies may suggest ways to alter the adult wound so that it heals in a fetal manner.     

Prostaglandin E2 differentially modulates human fetal and adult dermal fibroblast migration and contraction: implication for wound healing

Cyclooxygenase-2 is up-regulated shortly after dermal injury and it has been shown to have important activity during the repair process. Its main product in the skin, prostaglandin E2 (PGE2), modulates both inflammatory and fibrotic processes during wound healing and partially dictates the overall outcome of wound healing. PGE2 signaling has been shown to be altered during fetal wound healing. This study was designed to examine the mechanism(s) by which PGE2 regulates fibroblast migration and contraction and to determine whether these mechanisms are conserved in fetal-derived dermal fibroblasts. Fetal and adult dermal fibroblasts express all four PGE2 receptors. PGE2 inhibits fetal and adult fibroblast migration in a dose-dependent manner through the EP2/EP4-cAMP-protein kinase A pathway. However, fetal fibroblasts appear to be refractory to this effect, requiring a 10-fold higher concentration of PGE2 to achieve a similar degree of inhibition as adult fibroblasts. Inhibition of adult fibroblast migration correlated with disruption of the actin cytoskeleton. In contrast, PGE2 or a cAMP analog did not disrupt the actin cytoskeleton of fetal dermal fibroblasts. These findings were extended using a modified free-floating, fibroblast-populated collagen lattice (FPCL) contraction assay designed to measure fibroblast contraction. PGE2-inhibited FPCL contraction by adult fibroblasts, but fetal fibroblasts exhibited higher rates of FPCL contraction and a blunted response to exogenous modulation by PGE2 or a cyclase activator (forskolin). These findings indicate that fetal dermal fibroblasts are partially refractory to the effects of PGE2, a major inflammatory mediator associated with dermal wound healing. This effect may have significant and specific relevance to the scarless fetal wound-healing phenotype.     

Differential expression and regulation of extracellular matrix-associated genes in fetal and neonatal fibroblasts

Adults and neonates heal wounds by a repair process associated with scarring in contrast to scar-free wound healing in the fetus. In the present study, human dermal fetal fibroblasts, representing the scarless phenotype, and neonatal human dermal fibroblasts, representing scar-forming phenotype, were examined for potential differences that might influence the wound healing process. Fetal fibroblasts secreted four- to tenfold more latent transforming growth factor-beta1 depending on the cell strains compared. Fetal fibroblasts also produced higher levels of collagen protein and mRNA for most types of collagen (particularly type III) as compared to neonatal cells. Interestingly, mRNA for type V collagen was significantly reduced in fetal cells. Neonatal fibroblasts expressed significantly higher levels of latent transforming growth factor-beta1 binding protein mRNA, in contrast to almost undetectable levels in fetal fibroblasts. By ligand blot analysis, the levels of insulin-like growth factor binding protein-3, a reported mediator of transforming growth factor-beta1 activity, was eightfold higher in neonatal versus fetal fibroblasts. Approximately 20 other mRNAs for various cytokines, matrix molecules and receptors were examined and found to be similar between the two cell types. The phenotypic differences described in this article may represent potentially important mechanisms to explain the differences in the quality of wound repair observed in fetal versus adult/neonatal tissues.     

Permissive environment in postnatal wounds induced by adenoviral-mediated overexpression of the anti-inflammatory cytokine interleukin-10 prevents scar formation

Wound healing in the mid-gestation fetus is scarless with minimal inflammation and a unique extracellular matrix. We have previously documented the relative lack of inflammatory cytokines in this environment. We demonstrate that interleukin (IL)-10 is highly expressed in mid-gestation human fetal skin but is absent in postnatal human skin. We hypothesize that overexpression of IL-10 in postnatal skin may replicate a permissive environment for scarless healing. To study the mechanism underlying this process we performed immunohistochemistry for IL-10 in human mid-gestation fetal and postnatal skin. We also determined if adenoviral-mediated overexpression of IL-10 could allow for scarless wound healing in a murine incisional wound model. Wounds were analyzed at 1–90 days postwounding for effects on scar formation, inflammatory response, and biomechanical properties. Ad-IL-10 reconstitutes a permissive environment for scarless healing as shown by reconstitution of a normal dermal reticular collagen pattern and distribution of dermal elements. Compared with controls, Ad-IL-10 treated wounds showed reduced inflammatory response and no difference in biomechanical parameters. Therefore, overexpression of IL-10 in postnatal wounds results in a permissive environment for scarless wound repair, possibly by replicating a fetal wound environment.     

Fetal wound healing. The ontogeny of scar formation in the non-human primate.

OBJECTIVE: This study determined how scar formation develops in a non-human primate model of fetal skin repair. SUMMARY BACKGROUND DATA: A transition from healing scarlessly to healing with scar formation characterizes skin repair in rat and sheep fetuses. New knowledge of the regulatory processes occurring in the fetal wound at the initial stages of scar formation may provide insights into the early mechanisms of scar formation. METHODS: Full-thickness wounds were made in fetal rhesus monkey lips from 75 through 114 days gestation (n = 6, term = 165 days). Wounds were harvested at 14 days postwounding and processed for histology (hematoxylin & eosin, Masson's trichrome) as well as immunohistochemistry (human type I or type III collagen). RESULTS: Wounds healed with complete restoration of normal tissue architecture in the 75-day gestation fetus. However in the 85-100 day gestation fetuses, wounds healed with an absence of hair follicles and sebaceous glands, but the dermal collagen pattern remained reticular and similar to that in unwounded dermis. At 107 days, a thin scar was present in the wound, thereby demonstrating a transition to scar formation between 100 and 107 days gestation (early 3rd trimester) in the non-human primate. CONCLUSIONS: In the non-human primate fetus, a transition from scarless repair to adult-type repair with scar formation occurs in the early third trimester. These data provide insight into the transition process; the ontogeny of scar formation is characterized initially by wounds healing without the presence of epidermal appendages but with a normal reticular dermal collagen pattern, which we term the "transition wound."     

Differential regulation of free-floating collagen gel contraction by human fetal and adult dermal fibroblasts in response to prostaglandin E2 mediated by an EP2/cAMP-dependent mechanism

In contrast to fetal wound healing, dermal adult wound healing results in imperfect repair and scar formation. Fibroblasts are responsible for the contraction and remodeling of the wound matrix, which is influenced by inflammatory mediators including prostaglandin E2 (PGE2). This study addresses the mechanism by which PGE2 regulates contraction of collagen gels by human fetal and adult dermal fibroblasts. We hypothesized that the intrinsic phenotypic properties of the two types of fibroblasts and their responses to PGE2 alter their contraction properties and contribute to different wound healing outcomes. Contraction was evaluated using free-floating fibroblast-populated collagen gels that contract by migratory forces. PGE2 was found to differentially inhibit collagen gel contraction by fetal and adult fibroblasts. This effect was mimicked by a specific PGE2 receptor agonist as well as by two pharmacological agents, indicating a cyclic adenosine monophosphate-dependent signaling pathway mediated through the EP2 receptor. Our results indicate that fetal fibroblast contraction is maintained by a more stable actin cytoskeleton. Therefore, the migratory phenotype may be sufficient for physical remodeling of the wound matrix leading to regenerative repair. Maintenance of this phenotype in the later stages of wound healing could potentially be achieved by targeting cyclic adenosine monophosphate via the EP2 receptor.     

Analysis of collagen content in the fetal wound

The absence of apparent scar formation following the creation of surgical wounds in utero appears to be a phenomenon peculiarly privileged as a sequela of fetal wound healing. Little information exists to explain this disparity from our knowledge of adult wound healing. Therefore, following creation of surgical wounds in fetal rats, at different intervals the healing wounds were harvested and analyzed for collagen content and types. The average proportion of type III collagen was elevated in normal (26.5%) as well as wounded fetal skin (33.8%) when compared with normal levels for the adult (15%). The total collagen content was markedly diminished in the fetal wound. Although embryonal collagen synthesis apparently does exist in fetal reparative processes, the relationship to the lack of gross scarring remains undetermined.     

Wound healing in a fetal,adult, and scar tissue model: A comparative study

Early gestation fetal wounds heal without scar formation. Understanding the mechanism of this scarless healing may lead to new therapeutic strategies for improving adult wound healing. The aims of this study were to develop a human fetal wound model in which fetal healing can be studied and to compare this model with a human adult and scar tissue model. A burn wound (10 × 2 mm) was made in human ex vivo fetal, adult, and scar tissue under controlled and standardized conditions. Subsequently, the skin samples were cultured for 7, 14, and 21 days. Cells in the skin samples maintained their viability during the 21‐day culture period. Already after 7 days, a significantly higher median percentage of wound closure was achieved in the fetal skin model vs. the adult and scar tissue model (74% vs. 28 and 29%, respectively, p<0.05). After 21 days of culture, only fetal wounds were completely reepithelialized. Fibroblasts migrated into the wounded dermis of all three wound models during culture, but more fibroblasts were present earlier in the wound area of the fetal skin model. The fast reepithelialization and prompt presence of many fibroblasts in the fetal model suggest that rapid healing might play a role in scarless healing.     

Transplanted fibroblasts prevents dysfunctional repair in a murine CXCR3-deficient scarring model

In skin, the regeneration of the ontogenically distinct mesenchymal and epithelial compartments must proceed in a coordinated manner orchestrated by extracellular signaling networks. We have recently found that the switch from regeneration to remodeling during repair is modulated by chemokines that bind CXCR3 receptor. If this signaling is disrupted wounds continue to be active, resulting in a chronic hypercellular and hypertrophic state characterized by an immature matrix composition. As healing is masterminded in large part by fibroblasts and their synthesis of the extracellular matrix, the question arose as to whether this ongoing scarring can be modulated by transplanted fibroblasts. We examined wounds in the CXCR3-/- mouse scarring model. These wounds exhibited a significant delay in healing in all areas compared to young and aged wild-type mice. Full-thickness wounds were transplanted with fibroblasts derived from newborn CXCR3-/- or wild-type mice. The transplanted fibroblasts were labeled with fluorescent dye (CM-DiI) and suspended in hyaluronic acid gel; by 30 days, these transplanted cells comprised some 30% of the dermal stromal cells regardless of the host or source of transplanted cells. Wild-type fibroblasts transplanted into CXCR3-/- mice wounds reversed the delay and dysfunction previously seen in CXCR3-/- wounds; this correction was not noted with transplanted CXCR3-/- fibroblasts. Additionally, transplant of CXCR3-/- cells into wounds in wild-type animals did not adversely affect those wounds. The transplanted fibroblasts exhibited strong survival and migration patterns and led to an increase in tensile strength. Expression of matrix proteins and collagen in CXCR3-/- wounds transplanted with wild-type fibroblasts resembled normal wild-type healing, and the wound matrix in wild-type mice transplanted with CXCR3-/- cells also presented a mature matrix. These suggest that the major determinant of healing versus scarring lies with the nature of the matrix. These findings have intriguing implications for rational cellular interventions aimed at promoting wound healing via cell therapy.     

Fascial fibroblast kinetic activity is increased during abdominal wall repair compared to dermal fibroblasts

Abdominal wall fascial wound healing failure is a common clinical problem for general surgeons, manifesting in early postoperative fascial dehiscence as well as delayed development of incisional hernias. We previously reported that abdominal wall fascial incisions normally recover breaking strength faster than simultaneous dermal incisions in a rodent model. The accelerated fascial repair was associated with greater fibroblast cellularity within fascial wounds and increased wound collagen deposition. The current study was designed to determine whether accelerated fascial healing is the result of increased fascial fibroblast kinetic activity as measured by a more efficient fibroblast phenotype for binding to and remodeling a collagen matrix. Using a new model of abdominal wall repair, fibroblast cell cultures were developed from uninjured and wounded fascia and compared to dermal fibroblasts in order to define the fibroproliferative kinetic properties of abdominal wall fibroblasts. Fascial wound fibroblasts produced a more efficient and greater overall collagen lattice compaction compared to dermal fibroblasts. Acute fascial wound fibroblasts also showed enhanced cell proliferation compared to dermal fibroblasts but no significant differences in collagen production when normalized to cell number. These results suggest that fascial fibroblasts express distinct acute repair phenotypes and therefore a specific mechanism for fascial repair following injury.     

Thymosin β4 and a synthetic peptide containing its actin-binding domain promote dermal wound repair in db/db diabetic mice and in aged mice

Impaired wound healing is a problem for immobilized patients, diabetics, and the elderly. Thymosin beta 4 has previously been found to promote dermal and corneal repair in normal rats. Here we report that thymosin beta 4 was also active in accelerating wound repair in full-thickness dermal wounds in both db/db diabetic and aged mice. We found that thymosin beta 4 in either phosphate-buffered saline or a hydrogel formulation is active in promoting dermal wound repair in normal rats. In diabetic mice, where healing is delayed, we found that wound contracture and collagen deposition were significantly increased in the mice treated with thymosin beta 4 in either phosphate buffered saline solution or a hydrogel formulation. No difference was observed in keratinocyte migration, with all of the diabetic animals showing almost complete coverage of the wound at 8 days. Wound healing in 26-month-old (aged) animals was significantly delayed. Thymosin beta 4 accelerated wound healing in these aged mice, with increases in keratinocyte migration, wound contracture, and collagen deposition. The hydrogel formulation generally showed similar wound healing activity with thymosin beta 4 in PBS. The actin-binding domain of thymosin beta 4 duplicated in a seven-amino acid synthetic peptide, LKKTETQ, was able to promote repair in the aged animals comparable to that observed with the parent molecule. These studies show that thymosin beta 4 is active for wound repair in models of impaired healing and may have efficacy in chronic wounds in humans.     

Fetal diaphragmatic wounds heal with scar formation

Fetal wound healing is fundamentally different from wound healing in the adult. Although experimental work in mice, rats, rabbits, monkeys, and sheep has demonstrated that fetal healing occurs without inflammation and scarring, all of these studies have been limited to fetal skin wounds. Whether all fetal tissues heal in a regenerative-like fashion is unknown. Amniotic fluid exposure may play an important role in scarless fetal skin wound healing, but the effect of amniotic fluid on fetal mesothelial wound healing has not been characterized. To investigate these questions we created bilateral linear diaphragmatic wounds in 100-day gestation fetal lambs (term = 145 days). The right thoracotomy was closed to exclude amniotic fluid. In contrast, the left thoracotomy was fashioned into an Eloesser flap which permitted the left diaphragmatic wound to be continually bathed in amniotic fluid. Wounds were harvested after 1, 2, 7, or 14 days and analyzed by light microscopy and immunohistochemistry with antibodies to collagen types I, III, IV, and VI. Whether bathed in or excluded from amniotic fluid, the mesothelial-lined diaphragm healed with scar formation and without evidence of muscle regeneration. Interestingly, diaphragmatic wounds exposed to amniotic fluid were covered by a thick fibrous collagen peel similar to that seen in gastroschisis bowel. These findings indicate that not all fetal tissues share the unique scarless healing properties of fetal skin.     

Scarless human fetal skin repair is intrinsic to the fetal fibroblast and occurs in the absence of an inflammatory response

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 skin heals with scar formation when transplanted to a cutaneous location. In situ hybridization with species-specific DNA probes and immunohistochemistry were performed 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. We found that the cutaneous human fetal grafts healed with scar and showed an influx of 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. We conclude that the highly organized collagen deposition in scarless human fetal wound repair appears to be intrinsic to the human fetal fibroblasts and occurs in the absence of an adult-like inflammatory response.     

Basic fibroblast growth factor in an artificial dermis promotes apoptosis and inhibits expression of α-smooth muscle actin, leading to reduction of wound contraction

To clarify the mechanisms underlying declines in wound contraction caused by basic fibroblast growth factor (bFGF) and the role of autologous fibroblasts in modulating wound healing, we have examined the expression of alpha-smooth muscle actin (alpha-SMA) and apoptosis in a model of wound healing using collagen sponges with and without bFGF (1 microg) and/or fibroblasts (1 x 10(6) cells/cm(2)) applied to experimentally produced full-thickness skin wounds in rats (n=10 for each group). At 7 days postoperatively, wounds filled with a fibroblast-seeded collagen sponge (fibroblast-seeded group) displayed a greater area of collagen sponge and a smaller area of fibroblasts compared with control wounds filled with collagen sponge alone (control group). Therefore, seeding of fibroblasts in the dermal substitute might retard degradation of the collagen sponge, inhibiting fibroblast infiltration into the substitute. By day 14, wounds filled with bFGF-treated collagen sponge without fibroblast seeding (bFGF group) displayed decreased alpha-SMA expression and significantly increased apoptosis compared with other wounds. Double staining revealed that apoptosis in alpha-SMA-positive fibroblastic cells was significantly increased in the bFGF group, suggesting that bFGF treatment is a potent stimulator of myofibroblast apoptosis. Furthermore, morphometric analysis demonstrated the significant decrease in the level of wound contraction and the degree of mature collagen bundle formation in the bFGF group by day 42. The bFGF group also showed increased bFGF expression in macrophages by day 28. These results suggest that bFGF administration to an artificial dermis promotes apoptosis of alpha-SMA-positive fibroblastic cells and inhibits alpha-SMA expression in the treated wound, thus reducing wound contraction.     

Interleukin‐33 encourages scar formation in murine fetal skin wounds

The magnitude of the inflammatory response after skin injury is important for determining whether wounds in developing fetal skin will heal scarlessly (minimal inflammation) or with prominent scars (robust inflammation). One class of inflammatory mediators gaining attention for their role in wound inflammation is alarmins. In the current study, the alarmin interleukin‐33 (IL‐33) was examined in a mouse model of fetal wound healing. IL‐33 expression was elevated in scar‐forming embryonic day 18 wounds compared to scarless embryonic day 15 wounds. Furthermore, injection of IL‐33 into embryonic day 15 wounds caused scarring when wounds were analyzed at 7 days postwounding. The introduction of IL‐33 into embryonic day 15 wounds did not induce statistically significant changes in the number of neutrophils, mast cells, or macrophages in vivo. However, IL‐33 treatment enhanced collagen expression in cultured fibroblasts derived from adult and fetal murine skin, suggesting that IL‐33 may directly stimulate fibroblasts. In vitro studies suggested that the stimulation of collagen production by IL‐33 in fibroblasts was partially dependent on NF‐κB activation. Overall, the data suggest an association between IL‐33 and scar formation in fetal wounds.     

Midgestational excisional fetal lamb wounds contract in utero

Clinical observations and experimental data suggest that fetal wound healing is very different from adult wound healing. An understanding of the biology of scarless fetal wound healing has tremendous clinical potential for modulating postnatal wound problems. In this study, the fetal lamb model was used to assess excisional fetal skin wound contraction in utero. Full-thickness 9-mm punch biopsy wounds were created on fetal lambs at 100 days' gestation (term, 145 days). Half of the wounds remained exposed to amniotic fluid, whereas the other half were covered by a silastic patch to exclude amniotic fluid. Wounds were harvested 3, 7, or 14 days later and wound areas were calculated. Exposure to amniotic fluid retarded wound contraction significantly at 3 days, but by 14 days all wounds had completely contracted and reepithelialized. Myofibroblasts are an important cellular element of wound contraction. The presence of wound myofibroblasts was documented by both transmission electronmicroscopy and immunocytochemistry with antimuscle actin antibody. It is concluded that fetal lamb wounds contract in utero and exposure to amniotic fluid appears to retard fetal skin wound contraction only during the early healing process.