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Michael T. Longaker - One of the best experts on this subject based on the ideXlab platform.

  • scarless Wound healing transitioning from Fetal research to regenerative healing
    Wiley Interdisciplinary Reviews-Developmental Biology, 2018
    Co-Authors: Alessandra L Moore, Clement D Marshall, Leandra A Barnes, Matthew P Murphy, Ryan C Ransom, Michael T. Longaker
    Abstract:

    Since the discovery of scarless Fetal skin Wound healing, research in the field has expanded significantly with the hopes of advancing the finding to adult human patients. There are several differences between Fetal and adult skin that have been exploited to facilitate scarless healing in adults including growth factors, cytokines, and extracellular matrix substitutes. However, no one therapy, pathway, or cell subtype is sufficient to support scarless Wound healing in adult skin. More recently, products that contain or mimic Fetal and adult uninjured dermis were introduced to the Wound healing market with promising clinical outcomes. Through our review of the major experimental targets of Fetal Wound healing, we hope to encourage research in areas that may have a significant clinical impact. Additionally, we will investigate therapies currently in clinical use and evaluate whether they represent a legitimate advance in regenerative medicine or a vulnerary agent. WIREs Dev Biol 2018, 7:e309. doi: 10.1002/wdev.309 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Plant Development > Cell Growth and Differentiation Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells.

  • a mouse Fetal skin model of scarless Wound repair
    Journal of Visualized Experiments, 2015
    Co-Authors: Graham G Walmsley, Peter H Lorenz, Zeshaan N Maan, Wan Xing Hong, Michael T. Longaker
    Abstract:

    Early in utero, but not in postnatal life, cutaneous Wounds undergo regeneration and heal without formation of a scar. Scarless Fetal Wound healing occurs across species but is age dependent. The transition from a scarless to scarring phenotype occurs in the third trimester of pregnancy in humans and around embryonic day 18 (E18) in mice. However, this varies with the size of the Wound with larger defects generating a scar at an earlier gestational age. The emergence of lineage tracing and other genetic tools in the mouse has opened promising new avenues for investigation of Fetal scarless Wound healing. However, given the inherently high rates of morbidity and premature uterine contraction associated with Fetal surgery, investigations of Fetal scarless Wound healing in vivo require a precise and reproducible surgical model. Here we detail a reliable model of Fetal scarless Wound healing in the dorsum of E16.5 (scarless) and E18.5 (scarring) mouse embryos.

  • Scarless Fetal skin Wound healing update
    Birth defects research. Part C Embryo today : reviews, 2012
    Co-Authors: A.s. Zimmermann, Michael T. Longaker, Allison Nauta, H. Peter Lorenz
    Abstract:

    Scar formation, a physiologic process in adult Wound healing, can have devastating effects for patients; a multitude of pathologic outcomes, affecting all organ systems, stems from an amplification of this process. In contrast to adult Wound repair, the early-gestation Fetal skin Wound heals without scar formation, a phenomenon that appears to be intrinsic to Fetal skin. An intensive research effort has focused on unraveling the mechanisms that underlie scarless Fetal Wound healing in an attempt to improve the quality of healing in both children and adults. Unique properties of Fetal cells, extracellular matrix, cytokine profile, and gene expression contribute to this scarless repair. Despite the great increase in knowledge gained over the past decades, the precise mechanisms regulating scarless Fetal healing remain unknown. Herein, we describe the current proposed mechanisms underlying Fetal scarless Wound healing in an effort to recapitulate the Fetal phenotype in the postnatal environment. Birth Defects Research (Part C) 96:237–247, 2012. © 2012 Wiley Periodicals, Inc.

  • Fetal mouse skin heals scarlessly in a chick chorioallantoic membrane model system
    Annals of Plastic Surgery, 2012
    Co-Authors: Antoine L Carre, Michael T. Longaker, Barrett J Larson, Joseph A Knowles, Kenichiro Kawai, Peter H Lorenz
    Abstract:

    In mammals, the early-gestation fetus has the regenerative ability to heal skin Wounds without scar formation. This observation was first reported more than 3 decades ago, and has been confirmed in a number of in vivo animal models. Although an intensive research effort has focused on unraveling the mechanisms underlying scarless Fetal Wound repair, no suitable model of in vitro Fetal skin healing has been developed. In this article, we report a novel model for the study of Fetal Wound healing. Fetal skin from gestational day 16.5 Balb/c mice (total gestation, 20 days) was grafted onto the chorioallantoic membrane of 12-day-old chicken embryos and cultured for up to 7 days. At 48 hours postengraftment, circular Wounds (diameter = 1 mm) were made in the Fetal skin using a rotating titanium sapphire laser (N = 45). The tissue was examined daily by visual inspection to look for signs of infection and ischemia. The grafts and the surrounding host tissue were examined histologically. In all Fetal skin grafts, the Wounds completely reepithelialized by postinjury day 7, with regeneration of the dermis. Fetal mouse skin xenografts transplanted onto the chorioallantoic membrane of fertilized chicken eggs provides a useful model for the study of Fetal Wound healing. This model can be used as an adjunct to traditional in vivo mammalian models of Fetal repair.

  • Scarless Fetal Wound healing: a basic science review.
    Plastic and reconstructive surgery, 2010
    Co-Authors: Barrett J Larson, Michael T. Longaker, H. Peter Lorenz
    Abstract:

    Summary:Scar formation is a major medical problem that can have devastating consequences for patients. The adverse physiological and psychological effects of scars are broad, and there are currently no reliable treatments to prevent scarring. In contrast to adult Wounds, early gestation Fetal skin w

Kenneth W Liechty - One of the best experts on this subject based on the ideXlab platform.

  • modulation of the inflammatory response by increasing Fetal Wound size or interleukin 10 overexpression determines Wound phenotype and scar formation
    Wound Repair and Regeneration, 2014
    Co-Authors: Michael W Morris, Myron Allukian, Benjamin J Herdrich, Robert C Caskey, Carlos Zgheib, Wanda A Dorsettmartin, Marc E Mitchell, Kenneth W Liechty
    Abstract:

    Wound size impacts the threshold between scarless regeneration and reparative healing in the fetus with increased inflammation showed in Fetal scar formation. We hypothesized that increased Fetal Wound size increases pro-inflammatory and fibrotic genes with resultant inflammation and fibroplasia and that transition to scar formation could be reversed by overexpression of interleukin-10 (IL-10). To test this hypothesis, 2-mm and 8-mm dermal Wounds were created in mid-gestation Fetal sheep. A subset of 8-mm Wounds were injected with a lentiviral vector containing the IL-10 transgene (n = 4) or vehicle (n = 4). Wounds were harvested at 3 or 30 days for histology, immunohistochemistry, analysis of gene expression by microarray, and validation with real-time polymerase chain reaction. In contrast to the scarless 2-mm Wounds, 8-mm Wounds showed scar formation with a differential gene expression profile, increased inflammatory cytokines, decreased CD45+ cells, and subsequent inflammation. Lentiviral-mediated overexpression of the IL-10 gene resulted in conversion to a regenerative phenotype with decreased inflammatory cytokines and regeneration of dermal architecture. In conclusion, increased Fetal Wounds size leads to a unique gene expression profile that promotes inflammation and leads to scar formation and furthermore, these results show the significance of attenuated inflammation and IL-10 in the transition from fibroplasia to Fetal regenerative healing.

  • il 10 overexpression decreases inflammatory mediators and promotes regenerative healing in an adult model of scar formation
    Journal of Investigative Dermatology, 2008
    Co-Authors: William H Peranteau, Liping Zhang, Nidal Muvarak, Andrea T Badillo, Antoneta Radu, Philip W Zoltick, Kenneth W Liechty
    Abstract:

    Adult Wound healing is characterized by an exuberant inflammatory response and scar formation. In contrast, scarless Fetal Wound healing has diminished inflammation, a lack of fibroplasia, and restoration of normal architecture. We have previously shown that Fetal Wounds produce less inflammatory cytokines, and the absence of IL-10, an anti-inflammatory cytokine, results in Fetal scar formation. We hypothesized that increased IL-10 would decrease inflammation and create an environment conducive for regenerative healing in the adult. To test this hypothesis, a lentiviral vector expressing IL-10 and green fluorescent protein (GFP) (Lenti-IL-10) or GFP alone (Lenti-GFP) was injected at the Wound site 48hours before Wounding. We found that both Lenti-IL-10 and Lenti-GFP were expressed in the Wounds at 1 and 3 days post Wounding. At 3 days, Lenti-IL-10-treated Wounds demonstrated decreased inflammation and decreased quantities of all proinflammatory mediators analyzed with statistically different levels of IL-6, monocyte chemoattractant protein-1, and heat-shock protein 47. At 3 weeks, Lenti-GFP Wounds demonstrated scar formation. In contrast, Wounds injected with Lenti-IL-10 demonstrated decreased inflammation, a lack of abnormal collagen deposition, and restoration of normal dermal architecture. We conclude that lentivirus-mediated overexpression of IL-10 decreases the inflammatory response to injury, creating an environment conducive for regenerative adult Wound healing.

  • Fetal Wound repair results in scar formation in interleukin 10 deficient mice in a syngeneic murine model of scarless Fetal Wound repair
    Journal of Pediatric Surgery, 2000
    Co-Authors: Kenneth W Liechty, Scott N Adzick, Heung Bae Kim, Timothy M. Crombleholme
    Abstract:

    Abstract Background: Fetal dermal Wound healing is characterized by minimal inflammation, restoration of normal dermal architecture, and scarless repair. The authors have shown that proinflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) are diminished during Fetal Wound repair. Interleukin-10 (IL-10) is an antiinflammatory cytokine that decreases production of IL-6 and IL-8. The authors hypothesized that diminished IL-6 and IL-8 and minimal inflammation may be caused by IL-10. Methods: To test this hypothesis, the authors developed a new syngeneic murine model of Fetal Wound repair in which 15-day-gestation skin from either normal C57BL/6 or transgenic C57BL/6 IL-10 knockout mice was grafted to the back of the same strain adult mice. The grafts were incisionally Wounded after 5 days, harvested at 1 week, and analyzed for inflammatory response and scar formation. Results: Wounds in normal Fetal skin grafts showed minimal inflammation and normal dermal reticular collagen pattern at the site of the Wound, consistent with scarless repair. In contrast, Wounds in IL-10 knockout Fetal skin grafts showed significant inflammation and scar formation. Conclusions: Fetal skin grafts on adult syngeneic mice heal without inflammation or scar formation. The absence of IL-10 in Fetal skin results in scar formation. Intrinsic lack of IL-10 may result in continued amplification of the inflammatory cytokine cascade, continued stimulation of fibroblasts, and abnormal collagen deposition. IL-10 is necessary for scarless Wound repair to occur. J Pediatr Surg 35:866-873. Copyright © 2000 by W.B. Saunders Company.

  • diminished interleukin 6 il 6 production during scarless human Fetal Wound repair
    Cytokine, 2000
    Co-Authors: Kenneth W Liechty, Scott N Adzick, Timothy M. Crombleholme
    Abstract:

    Fetal Wound healing is characterized by minimal inflammation and scarless repair. IL-6 stimulates inflammation in postnatal Wound healing. We hypothesized that Fetal skin has a diminished IL-6 response and that exogenous IL-6 will result in scar formation. Human adult or Fetal skin was placed subcutaneously in SCID mice and incisionally Wounded. Wounds were excised after 4, 12, 24 or 72 h for IL-6 mRNA quantification by RT-PCR. In other grafts, 5 microgram of IL-6 was injected at Wounding and then harvested at 7 days for analysis of scar formation. IL-6 production was examined in primary cultures of human Fetal or adult dermal fibroblasts incubated for 8 h with 0, 0.1, 1 or 10 ng/ml of PDGF-BB. IL-6 mRNA was detected 4 h after Wounding in Fetal and adult Wounds, but by 12 h there was no IL-6 mRNA in the Fetal Wounds. Adult Wounds had IL-6 mRNA persisting to 72 h. IL-6 administration to Fetal Wounds resulted in scar formation. Fetal fibroblasts produced less IL-6 protein and mRNA at all points examined (P<0.01 vs adult). Diminished production of inflammatory cytokines such as IL-6 may be responsible for the lack of inflammation seen during Fetal Wound healing. Diminished inflammation may provide a permissive environment for scarless Wound healing.

  • diminished interleukin 8 il 8 production in the Fetal Wound healing response
    Journal of Surgical Research, 1998
    Co-Authors: Kenneth W Liechty, Timothy M. Crombleholme, Darrell L. Cass, Bernard Martin, Scott N Adzick
    Abstract:

    Abstract Background.Fetal skin Wound healing results in scarless repair with minimal cellular inflammatory response. Interleukin-8 (IL-8) stimulates inflammation in postnatal Wound healing but little is known about its role in Fetal Wounds. We hypothesized that Fetal tissues have diminished IL-8 during Wound repair and in response to platelet-derived growth factor (PDGF), a growth factor central to Wound healing. Materials and methods.To examine the IL-8 response of fibroblasts to PDGF, cultures of human Fetal (17–18 weeks) and adult dermal fibroblasts were incubated 8 h with PDGF (0, 0.1, 1, or 10 ng/mL) and supernatants and cells were collected for IL-8 ELISA and IL-8 RT-PCR. To evaluate the IL-8 response to Wounding, human adult and Fetal skin was placed subcutaneously in the SCID mouse, Wounded, and the Wound cleft excised after 4, 12, 24, or 72 h for IL-8 RT-PCR. Results.Fetal fibroblasts produced less IL-8 protein at baseline (50 ± 6 pg/mL versus 450 ± 115 pg/mL,P Conclusions.Diminished inflammatory cytokine response by Fetal tissues may be responsible for the lack of cellular recruitment and inflammation seen in Fetal Wound healing and may contribute to scarless Wound repair.

Scott N Adzick - One of the best experts on this subject based on the ideXlab platform.

  • Fetal Wound repair results in scar formation in interleukin 10 deficient mice in a syngeneic murine model of scarless Fetal Wound repair
    Journal of Pediatric Surgery, 2000
    Co-Authors: Kenneth W Liechty, Scott N Adzick, Heung Bae Kim, Timothy M. Crombleholme
    Abstract:

    Abstract Background: Fetal dermal Wound healing is characterized by minimal inflammation, restoration of normal dermal architecture, and scarless repair. The authors have shown that proinflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) are diminished during Fetal Wound repair. Interleukin-10 (IL-10) is an antiinflammatory cytokine that decreases production of IL-6 and IL-8. The authors hypothesized that diminished IL-6 and IL-8 and minimal inflammation may be caused by IL-10. Methods: To test this hypothesis, the authors developed a new syngeneic murine model of Fetal Wound repair in which 15-day-gestation skin from either normal C57BL/6 or transgenic C57BL/6 IL-10 knockout mice was grafted to the back of the same strain adult mice. The grafts were incisionally Wounded after 5 days, harvested at 1 week, and analyzed for inflammatory response and scar formation. Results: Wounds in normal Fetal skin grafts showed minimal inflammation and normal dermal reticular collagen pattern at the site of the Wound, consistent with scarless repair. In contrast, Wounds in IL-10 knockout Fetal skin grafts showed significant inflammation and scar formation. Conclusions: Fetal skin grafts on adult syngeneic mice heal without inflammation or scar formation. The absence of IL-10 in Fetal skin results in scar formation. Intrinsic lack of IL-10 may result in continued amplification of the inflammatory cytokine cascade, continued stimulation of fibroblasts, and abnormal collagen deposition. IL-10 is necessary for scarless Wound repair to occur. J Pediatr Surg 35:866-873. Copyright © 2000 by W.B. Saunders Company.

  • diminished interleukin 6 il 6 production during scarless human Fetal Wound repair
    Cytokine, 2000
    Co-Authors: Kenneth W Liechty, Scott N Adzick, Timothy M. Crombleholme
    Abstract:

    Fetal Wound healing is characterized by minimal inflammation and scarless repair. IL-6 stimulates inflammation in postnatal Wound healing. We hypothesized that Fetal skin has a diminished IL-6 response and that exogenous IL-6 will result in scar formation. Human adult or Fetal skin was placed subcutaneously in SCID mice and incisionally Wounded. Wounds were excised after 4, 12, 24 or 72 h for IL-6 mRNA quantification by RT-PCR. In other grafts, 5 microgram of IL-6 was injected at Wounding and then harvested at 7 days for analysis of scar formation. IL-6 production was examined in primary cultures of human Fetal or adult dermal fibroblasts incubated for 8 h with 0, 0.1, 1 or 10 ng/ml of PDGF-BB. IL-6 mRNA was detected 4 h after Wounding in Fetal and adult Wounds, but by 12 h there was no IL-6 mRNA in the Fetal Wounds. Adult Wounds had IL-6 mRNA persisting to 72 h. IL-6 administration to Fetal Wounds resulted in scar formation. Fetal fibroblasts produced less IL-6 protein and mRNA at all points examined (P<0.01 vs adult). Diminished production of inflammatory cytokines such as IL-6 may be responsible for the lack of inflammation seen during Fetal Wound healing. Diminished inflammation may provide a permissive environment for scarless Wound healing.

  • diminished interleukin 8 il 8 production in the Fetal Wound healing response
    Journal of Surgical Research, 1998
    Co-Authors: Kenneth W Liechty, Timothy M. Crombleholme, Darrell L. Cass, Bernard Martin, Scott N Adzick
    Abstract:

    Abstract Background.Fetal skin Wound healing results in scarless repair with minimal cellular inflammatory response. Interleukin-8 (IL-8) stimulates inflammation in postnatal Wound healing but little is known about its role in Fetal Wounds. We hypothesized that Fetal tissues have diminished IL-8 during Wound repair and in response to platelet-derived growth factor (PDGF), a growth factor central to Wound healing. Materials and methods.To examine the IL-8 response of fibroblasts to PDGF, cultures of human Fetal (17–18 weeks) and adult dermal fibroblasts were incubated 8 h with PDGF (0, 0.1, 1, or 10 ng/mL) and supernatants and cells were collected for IL-8 ELISA and IL-8 RT-PCR. To evaluate the IL-8 response to Wounding, human adult and Fetal skin was placed subcutaneously in the SCID mouse, Wounded, and the Wound cleft excised after 4, 12, 24, or 72 h for IL-8 RT-PCR. Results.Fetal fibroblasts produced less IL-8 protein at baseline (50 ± 6 pg/mL versus 450 ± 115 pg/mL,P Conclusions.Diminished inflammatory cytokine response by Fetal tissues may be responsible for the lack of cellular recruitment and inflammation seen in Fetal Wound healing and may contribute to scarless Wound repair.

  • the human homeobox genes msx 1 msx 2 and mox 1 are differentially expressed in the dermis and epidermis in Fetal and adult skin
    Differentiation, 1997
    Co-Authors: Eric J Stelnicki, Michael R. Harrison, Scott N Adzick, Laszlo G Komuves, Dennis R Holmes, Whitney Clavin, Corey Largman
    Abstract:

    In order to identify homeobox genes which may regulate skin development and possibly mediate scarless Fetal Wound healing we have screened amplified human Fetal skin cDNAs by polymerase chain reaction (PCR) using degenerate oligonucleotide primers designed against highly conserved regions within the homeobox. We identified three non-HOX homeobox genes, MSX-1, MSX-2, and MOX-1, which were differentially expressed in Fetal and adult human skin. MSX-1 and MSX-2 were detected in the epidermis, hair follicles, and fibroblasts of the developing Fetal skin by in situ hybridization. In contrast, MSX-1 and MSX-2 expression in adult skin was confined to epithelially derived structures. Immunohistochemical analysis of these two genes suggested that their respective homeoproteins may be differentially regulated. While Msx-1 was detected in the cell nucleus of both Fetal and adult skin; Msx-2 was detected as a diffuse cytoplasmic signal in Fetal epidermis and portions of the hair follicle and dermis, but was localized to the nucleus in adult epidermis. MOX-1 was expressed in a pattern similar to MSX early in gestation but then was restricted exclusively to follicular cells in the innermost layer of the outer root sheath by 21 weeks of development. Furthermore, MOX-1 expression was completely absent in adult cutaneous tissue. These data imply that each of these homeobox genes plays a specific role in skin development.

  • a model of scarless human Fetal Wound repair is deficient in transforming growth factor beta
    Journal of Pediatric Surgery, 1995
    Co-Authors: Kerry M Sullivan, Martin Meuli, Richard Y. Lin, Peter H Lorenz, Scott N Adzick
    Abstract:

    Abstract Human Fetal skin heals via scarless regeneration, whereas adult skin heals with scar. Scarless repair may reflect a distinct cytokine milieu. We studied the role of the cytokine transforming growth factor beta (TGFβ) using an established model of scarless human Fetal skin repair in which human Fetal skin is transplanted into a subcutaneous pocket on the flank of an adult nude mouse. In this model, Wounded 16-week-gestation human Fetal skin heals without scar, whereas Wounded adult skin heals with scar. Seven days after transplantation, incisional Wounds were made in the skin grafts. In the first phase of the study, Wounds were harvested from 1 hour to 4 weeks postWounding, and immunohistochemistry was performed for TGFβ (isoform nonspecific), TGFβ 1 , and TGFβ 2 . Scarfree Wounds in the Fetal skin grafts did not show TGFβ staining. In contrast, Wounds in adult grafts that heal with scar demonstrated isoform nonspecific TGFβ staining from 6 hours through 21 days, TGFβ 1 from 6 hours through 21 days, and TGFβ 2 from 12 hours through 7 days. In the second phase of the study, a slow-release disk with 0.01, 0.1, 1.0, or 10 μg of TGFβ 1 was placed beneath the Fetal skin graft at the time of Wounding. Fourteen days postWounding, there was marked scarring in the Fetal grafts treated with TGFβ 1 , and the size of the scar was proportional to the amount of TGFβ 1 applied. The relative lack of TGFβ, a cytokine known to promote fibrosis, may be one reason why the fetus heals by regeneration rather than scarring. In contrast, the fibrosis characteristic of postnatal Wound repair may be associated with an excess of TGFβ. These findings suggest that anti-TGFβ therapeutic strategies may ameliorate scar formation in children and adults.

Timothy M. Crombleholme - One of the best experts on this subject based on the ideXlab platform.

  • Fetal Wound healing implications for minimal scar formation
    Current Opinion in Pediatrics, 2012
    Co-Authors: A Leung, Timothy M. Crombleholme, Sundeep G. Keswani
    Abstract:

    Purpose of review The mid-gestation fetus is capable of regenerative healing with Wound healing indistinguishable from surrounding skin. This review aims to evaluate the current knowledge of how the mid-gestation fetus heals without scar and the implications of these findings in efforts to recapitulate the Fetal regenerative phenotype in the postnatal environment.

  • Expression of human collagenase-3 (MMP-13) by Fetal skin fibroblasts is induced by transforming growth factor beta via p38 mitogen-activated protein kinase.
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2001
    Co-Authors: Laura Ravanti, Timothy M. Crombleholme, Mervi Toriseva, Risto Penttinen, Marco Foschi, Jiahuai Han, Veli-matti Kähäri
    Abstract:

    SPECIFIC AIMSIn the present study we have examined the possible role of collagenase-3 (matrix metalloproteinase-13; MMP-13), a collagenolytic MMP with a wide substrate specificity, in human Fetal skin Wound repair characterized by minimal scar formation. The expression of MMP-13 was examined in Wounds in human Fetal skin grafted on SCID mice, and the regulation of human MMP-13 expression was examined in Fetal skin fibroblasts in culture.PRINCIPAL FINDINGS1. Human MMP-13 is expressed by fibroblasts in Fetal skin WoundsTo elucidate the role and regulation of human MMP-13 in Fetal Wound repair, which is characterized by minimal scar formation, we first examined the expression of MMP-13 in a well-characterized model of normally healing incisional Wound of human Fetal skin (16 to 20 wk of gestational age) grafted on SCID mice. MMP-13-positive fibroblasts were detected by immunostaining within the dermal layer in 4-day-old Wounds (Fig. 1A⤻ , B⤻ ). Numerous MMP-13-positive dermal fibroblasts were also detected i...

  • Fetal Wound repair results in scar formation in interleukin 10 deficient mice in a syngeneic murine model of scarless Fetal Wound repair
    Journal of Pediatric Surgery, 2000
    Co-Authors: Kenneth W Liechty, Scott N Adzick, Heung Bae Kim, Timothy M. Crombleholme
    Abstract:

    Abstract Background: Fetal dermal Wound healing is characterized by minimal inflammation, restoration of normal dermal architecture, and scarless repair. The authors have shown that proinflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) are diminished during Fetal Wound repair. Interleukin-10 (IL-10) is an antiinflammatory cytokine that decreases production of IL-6 and IL-8. The authors hypothesized that diminished IL-6 and IL-8 and minimal inflammation may be caused by IL-10. Methods: To test this hypothesis, the authors developed a new syngeneic murine model of Fetal Wound repair in which 15-day-gestation skin from either normal C57BL/6 or transgenic C57BL/6 IL-10 knockout mice was grafted to the back of the same strain adult mice. The grafts were incisionally Wounded after 5 days, harvested at 1 week, and analyzed for inflammatory response and scar formation. Results: Wounds in normal Fetal skin grafts showed minimal inflammation and normal dermal reticular collagen pattern at the site of the Wound, consistent with scarless repair. In contrast, Wounds in IL-10 knockout Fetal skin grafts showed significant inflammation and scar formation. Conclusions: Fetal skin grafts on adult syngeneic mice heal without inflammation or scar formation. The absence of IL-10 in Fetal skin results in scar formation. Intrinsic lack of IL-10 may result in continued amplification of the inflammatory cytokine cascade, continued stimulation of fibroblasts, and abnormal collagen deposition. IL-10 is necessary for scarless Wound repair to occur. J Pediatr Surg 35:866-873. Copyright © 2000 by W.B. Saunders Company.

  • diminished interleukin 6 il 6 production during scarless human Fetal Wound repair
    Cytokine, 2000
    Co-Authors: Kenneth W Liechty, Scott N Adzick, Timothy M. Crombleholme
    Abstract:

    Fetal Wound healing is characterized by minimal inflammation and scarless repair. IL-6 stimulates inflammation in postnatal Wound healing. We hypothesized that Fetal skin has a diminished IL-6 response and that exogenous IL-6 will result in scar formation. Human adult or Fetal skin was placed subcutaneously in SCID mice and incisionally Wounded. Wounds were excised after 4, 12, 24 or 72 h for IL-6 mRNA quantification by RT-PCR. In other grafts, 5 microgram of IL-6 was injected at Wounding and then harvested at 7 days for analysis of scar formation. IL-6 production was examined in primary cultures of human Fetal or adult dermal fibroblasts incubated for 8 h with 0, 0.1, 1 or 10 ng/ml of PDGF-BB. IL-6 mRNA was detected 4 h after Wounding in Fetal and adult Wounds, but by 12 h there was no IL-6 mRNA in the Fetal Wounds. Adult Wounds had IL-6 mRNA persisting to 72 h. IL-6 administration to Fetal Wounds resulted in scar formation. Fetal fibroblasts produced less IL-6 protein and mRNA at all points examined (P<0.01 vs adult). Diminished production of inflammatory cytokines such as IL-6 may be responsible for the lack of inflammation seen during Fetal Wound healing. Diminished inflammation may provide a permissive environment for scarless Wound healing.

  • diminished interleukin 8 il 8 production in the Fetal Wound healing response
    Journal of Surgical Research, 1998
    Co-Authors: Kenneth W Liechty, Timothy M. Crombleholme, Darrell L. Cass, Bernard Martin, Scott N Adzick
    Abstract:

    Abstract Background.Fetal skin Wound healing results in scarless repair with minimal cellular inflammatory response. Interleukin-8 (IL-8) stimulates inflammation in postnatal Wound healing but little is known about its role in Fetal Wounds. We hypothesized that Fetal tissues have diminished IL-8 during Wound repair and in response to platelet-derived growth factor (PDGF), a growth factor central to Wound healing. Materials and methods.To examine the IL-8 response of fibroblasts to PDGF, cultures of human Fetal (17–18 weeks) and adult dermal fibroblasts were incubated 8 h with PDGF (0, 0.1, 1, or 10 ng/mL) and supernatants and cells were collected for IL-8 ELISA and IL-8 RT-PCR. To evaluate the IL-8 response to Wounding, human adult and Fetal skin was placed subcutaneously in the SCID mouse, Wounded, and the Wound cleft excised after 4, 12, 24, or 72 h for IL-8 RT-PCR. Results.Fetal fibroblasts produced less IL-8 protein at baseline (50 ± 6 pg/mL versus 450 ± 115 pg/mL,P Conclusions.Diminished inflammatory cytokine response by Fetal tissues may be responsible for the lack of cellular recruitment and inflammation seen in Fetal Wound healing and may contribute to scarless Wound repair.

Traci A. Wilgus - One of the best experts on this subject based on the ideXlab platform.

  • a murine incisional Fetal Wound healing model to study scarless and fibrotic skin repair
    Methods of Molecular Biology, 2021
    Co-Authors: Traci A. Wilgus
    Abstract:

    The ideal response to skin injury is the complete regeneration of normal tissue without scar formation. This regenerative response is known to occur at early stages of embryonic development but is lost as the skin becomes more mature. In more developed skin, the Wound-healing response is suboptimal and results in the formation of scar tissue. Scar tissue can be a significant clinical concern, causing skin dysfunction as well as psychosocial issues related to poor aesthetic outcomes. Mouse models of Fetal Wound healing can be useful for understanding what regulatory pathways lead to skin regeneration and scarless healing in less developed skin or scarring and fibrotic healing in more developed skin. Here, a reproducible incisional Wound model in developing mice is described that our lab has used repeatedly to study scarless and fibrotic Fetal Wound healing.

  • Fetal Wound healing
    2020
    Co-Authors: Traci A. Wilgus
    Abstract:

    Abstract Cutaneous Wound healing is an active and clinically relevant area of research. Issues related to Wound healing, including chronic Wounds and excessive scarring, are commonly observed in patients. In mature skin, Wounds heal through a series of events that include inflammation, proliferation, and production/remodeling of the extracellular matrix, ending with the formation of a permanent collagenous scar. In developing Fetal skin, the healing process is altered such that Wounds are capable of healing by regeneration, which results in scar-free healing. While the precise mechanisms that allow for regenerative healing in Fetal skin remain unknown, published data suggest that a combination of the Wound microenvironment (i.e., limited inflammation and altered extracellular matrix components) and inherent differences in Fetal fibroblasts may be important. This chapter will provide a brief historical overview of mammalian Fetal Wound-healing research and review recent findings in the field.

  • interleukin 33 encourages scar formation in murine Fetal skin Wounds
    Wound Repair and Regeneration, 2019
    Co-Authors: Brian C Wulff, Nicholas K Pappa, Traci A. Wilgus
    Abstract:

    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.

  • the alarmin hmgb 1 influences healing outcomes in Fetal skin Wounds
    Wound Repair and Regeneration, 2013
    Co-Authors: Adrienne D Dardenne, Brian C Wulff, Traci A. Wilgus
    Abstract:

    In mice, cutaneous Wounds generated early in development (embryonic day 15, E15) heal scarlessly, while Wounds generated late in gestation (embryonic day 18, E18) heal with scar formation. Even though both types of Wounds are generated in the same sterile uterine environment, scarless Fetal Wounds heal without inflammation, but a strong inflammatory response is observed in scar-forming Fetal Wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age-related changes in inflammation and healing outcomes in Fetal skin. The purpose of this study was to determine whether the alarmin high-mobility group box-1 (HMGB-1) is involved in Fetal Wound repair. Immunohistochemical analysis showed that in unWounded skin, E18 keratinocytes expressed higher levels of HMGB-1 compared with E15 keratinocytes. After injury, HMGB-1 was released to a greater extent from keratinocytes at the margin of scar-forming E18 Wounds, compared with scarless E15 Wounds. Furthermore, instead of healing scarlessly, E15 Wounds healed with scars when treated with HMGB-1. HMGB-1-injected Wounds also had more fibroblasts, blood vessels, and macrophages compared with control Wounds. Together, these data suggest that extracellular HMGB-1 levels influence the quality of healing in cutaneous Wounds.

  • examining the role of mast cells in Fetal Wound healing using cultured cells in vitro
    Methods of Molecular Biology, 2013
    Co-Authors: Brian C Wulff, Traci A. Wilgus
    Abstract:

    Mast cells play an important role during the inflammatory phase of Wound healing, and studies suggest that they also influence scar formation and remodeling. Recently, our laboratory has characterized the mast cell response to injury in a Fetal Wound healing model. In this model, early gestation Fetal skin regenerates and heals without a scar (scarless Wounds) and late gestation skin heals with a scar (fibrotic Wounds). Differences in mast cell number, maturity, and activity were identified between scarless and scar-forming Fetal Wounds. To study mast cell function in more detail, in vitro experiments are useful. This chapter outlines methods to expand, purify, and study the function of mast cells harvested from murine Fetal skin. Using these methods, cultured mast cells retain many of the differences in maturity and activation seen during Fetal skin development in vivo. Studying the function of mast cells in vitro could help define the mechanisms by which mast cells contribute to Wound repair and ultimately lead to better therapies for improving Wound repair and reducing scar formation.