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Michael T. Longaker - One of the best experts on this subject based on the ideXlab platform.
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Induction of the Fetal Scarless Phenotype in Adult Wounds: Impossible?
Regenerative Medicine and Plastic Surgery, 2019Co-Authors: Mimi R. Borrelli, Michael T. Longaker, H P LorenzAbstract:Adult cutaneous Wounds repair through a fibroproliferative response which results in a scar. Early-gestation fetal skin has the ability to regenerate damaged skin without the formation of a scar in a process that resembles regeneration. The fetal and Adult Wound healing phenotypes are characterized by differences in the degree of inflammation, molecular signaling, extracellular matrix composition, and biomechanical properties. Significant advancements in understanding scarless fetal mammalian Wound healing have led to the development of therapeutic applications with the potential to reduce scarring in the healing of Adult cutaneous Wounds. This chapter outlines the molecular and cellular processes involved in scarless fetal Wound healing and the progress that has been made in recapitulating this process in Adult Wounds.
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Mechanical Forces in Cutaneous Wound Healing: Emerging Therapies to Minimize Scar Formation
Advances in Wound Care, 2018Co-Authors: Leandra A. Barnes, Michael T. Longaker, Clement D. Marshall, Tripp Leavitt, Alessandra L. Moore, Jennifer G. Gonzalez, Geoffrey C. GurtnerAbstract:Significance: Excessive scarring is major clinical and financial burden in the United States. Improved therapies are necessary to reduce scarring, especially in patients affected by hypertrophic and keloid scars. Recent Advances: Advances in our understanding of mechanical forces in the Wound environment enable us to target mechanical forces to minimize scar formation. Fetal Wounds experience much lower resting stress when compared with Adult Wounds, and they heal without scars. Therapies that modulate mechanical forces in the Wound environment are able to reduce scar size. Critical Issues: Increased mechanical stresses in the Wound environment induce hypertrophic scarring via activation of mechanotransduction pathways. Mechanical stimulation modulates integrin, Wingless-type, protein kinase B, and focal adhesion kinase, resulting in cell proliferation and, ultimately, fibrosis. Therefore, the development of therapies that reduce mechanical forces in the Wound environment would decrease the risk of developing excessive scars. Future Directions: The development of novel mechanotherapies is necessary to minimize scar formation and advance Adult Wound healing toward the scarless ideal. Mechanotransduction pathways are potential targets to reduce excessive scar formation, and thus, continued studies on therapies that utilize mechanical offloading and mechanomodulation are needed.
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Differences in Foetal, Adult Skin and Mucosal Repair
Stem Cell Biology and Tissue Engineering in Dental Sciences, 2015Co-Authors: A.s. Zimmermann, Michael T. Longaker, H. Peter LorenzAbstract: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. Interestingly, there is strong evidence to suggest healing of oral mucosal Wounds parallels that of fetal skin Wound repair, and that the relative scarless repair of oral mucosa is also derived primarily from the intrinsic differences in oral mucosal tissue, rather than from the intraoral environment. 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 skin and oral mucosal 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 Wound healing remain unknown. Herein, we describe the current models and proposed mechanisms underlying scarless Wound healing in an effort to better understand this privileged phenotype.
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Scarless fetal skin Wound healing update
Birth defects research. Part C Embryo today : reviews, 2012Co-Authors: A.s. Zimmermann, Michael T. Longaker, Allison Nauta, H. Peter LorenzAbstract: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.
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Chapter 6 Fetal Skin Wound Healing
Advances in clinical chemistry, 2009Co-Authors: Edward P. Buchanan, Michael T. Longaker, H P LorenzAbstract:1. Abstract The developing fetus has the ability to heal Wounds by regenerating normal epidermis and dermis with restoration of the extracellular matrix (ECM) architecture, strength, and function. In contrast, Adult Wounds heal with fibrosis and scar. Scar tissue remains weaker than normal skin with an altered ECM composition. Despite extensive investigation, the mechanism of fetal Wound healing remains largely unknown. We do know that early in gestation, fetal skin is developing at a rapid pace and the ECM is a loose network facilitating cellular migration. Wounding in this unique environment triggers a complex cascade of tightly controlled events culminating in a scarless Wound phenotype of fine reticular collagen and abundant hyaluronic acid. Comparison between postnatal and fetal Wound healing has revealed differences in inflammatory response, cellular mediators, cytokines, growth factors, and ECM modulators. Investigation into cell signaling pathways and transcription factors has demonstrated differences in secondary messenger phosphorylation patterns and homeobox gene expression. Further research may reveal novel genes essential to scarless repair that can be manipulated in the Adult Wound and thus ameliorate scar.
Magda M. W. Ulrich - One of the best experts on this subject based on the ideXlab platform.
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Wound healing in a fetal Adult and scar tissue model a comparative study
Wound Repair and Regeneration, 2010Co-Authors: Neeltje A. Coolen, Kelly C. W. M. Schouten, Bouke K. H. L. Boekema, Esther Middelkoop, Magda M. W. UlrichAbstract: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.
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Wound healing in a fetal, Adult, and scar tissue model: A comparative study
Wound Repair and Regeneration, 2010Co-Authors: Neeltje A. Coolen, Kelly C. W. M. Schouten, Bouke K. H. L. Boekema, Esther Middelkoop, Magda M. W. UlrichAbstract: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
Sandeep Kathju - One of the best experts on this subject based on the ideXlab platform.
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Scarless integumentary Wound healing in the mammalian fetus: Molecular basis and therapeutic implications
Birth defects research. Part C Embryo today : reviews, 2012Co-Authors: Sandeep Kathju, Phillip H. Gallo, Latha SatishAbstract:Adult mammals respond to injury of their skin/integument by forming scar tissue. Scar is useful in rapidly sealing an injured area, but can also lead to significant morbidity. Mammals in fetal life retain the ability to heal integumentary Wounds regeneratively, without scar. The critical molecular mechanisms governing this remarkable phenomenon have been a subject of great interest, in the hopes that these could be dissected and recapitulated in the healing Adult Wound, with the goal of inducing scarless healing in injured patients. Multiple lines of investigation spanning decades have implicated a number of factors in distinguishing scarless from fibrotic Wound healing, including most prominently transforming growth factor-β and interleukin-10, among others. Therapeutic interventions to try to mitigate scarring in Adult Wounds have been developed out of these studies, and have reached the level of clinical trials in humans, although as yet no FDA-approved treatment exists. More recent expressomic studies have revealed many more genes that are differentially expressed in scarlessly healing fetal Wounds compared with Adult, and microRNAs have also been identified as participating in the fetal Wound healing response. These represent an even greater range of potential therapeutics (or targets for therapy) to translate the promise of scarless fetal Wound healing to the injured Adult patient. Birth Defects Research (Part C) 96:223–236, 2012. © 2012 Wiley Periodicals, Inc.
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Cellular and Molecular Characteristics of Scarless versus Fibrotic Wound Healing
Dermatology research and practice, 2010Co-Authors: Latha Satish, Sandeep KathjuAbstract:The purpose of this paper is to compare and contrast the discrete biology differentiating fetal Wound repair from its Adult counterpart. Integumentary Wound healing in mammalian fetuses is essentially different from Wound healing in Adult skin. Adult (postnatal) skin Wound healing is a complex and well-orchestrated process spurred by attendant inflammation that leads to Wound closure with scar formation. In contrast, fetal Wound repair occurs with minimal inflammation, faster re-epithelialization, and without the accumulation of scar. Although research into scarless healing began decades ago, the critical molecular mechanisms driving the process of regenerative fetal healing remain uncertain. Understanding the molecular and cellular events during regenerative healing may provide clues that one day enable us to modulate Adult Wound healing and consequently reduce scarring.
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Cloning and expression of rabbit CCT subunits eta and beta in healing cutaneous Wounds
Cell Stress and Chaperones, 2010Co-Authors: Latha Satish, Sandra Johnson, Adam Abdulally, J. Christopher Post, Garth D. Ehrlich, Sandeep KathjuAbstract:We have previously identified the CCT subunit eta as specifically reduced in healing fetal skin Wounds by differential display, and observed that this reduction is not seen with any other CCT subunit. We now report the cloning and characterization of the cDNAs for rabbit CCT-eta and its closest evolutionary homolog, CCT-beta. Quantitative examination of CCT-eta and –beta message expression in healing fetal and Adult Wounds at 12 h post-injury confirms that CCT-eta mRNA is decreased in fetal Wound tissues, but actually elevated in Adult Wound tissues. CCT-beta mRNA, in contrast, remains unchanged in both fetal and Adult Wound tissues. CCT-eta mRNA remains persistently elevated in healing Adult Wounds for 28 days following injury, whereas CCT-beta mRNA remains invariant throughout. CCT-eta protein is similarly increased, whereas CCT-beta protein remains unchanged. -smooth muscle actin ( -SMA), a recognized substrate of CCT known to be important in integumentary Wound healing, was also measured over the course of Wound healing, and both mRNA and protein levels were elevated throughout the 28 days.
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differential expression of chaperonin containing t complex polypeptide cct subunits during fetal and Adult skin Wound healing
Cell Stress & Chaperones, 2008Co-Authors: Latha Satish, Sandra Johnson, Adam Abdulally, Garth D. Ehrlich, Duane Oswald, Christopher J Post, Sandeep KathjuAbstract:Integumentary Wound healing in early fetal life is regenerative and proceeds without scar formation. Expressomic analysis of this phenomenon by differential display has previously determined that the eta subunit of the cytosolic chaperonin containing T-complex polypeptide (CCT) is downregulated in the healing fetal Wound milieu. We now report that no other CCT subunit shares this distinct pattern of gene regulation as determined by limiting dilution reverse transcriptase polymerase chain reaction (RT-PCR); all seven of the remaining CCT subunits demonstrate no change in messenger RNA (mRNA) expression in healing fetal Wounds compared to unWounded control tissue. The alpha subunit, however, did evidence reduced message levels in healing Adult Wound tissue. We herein report on the cloning and sequence of the complementary DNA (cDNA) for rabbit CCT-alpha and confirm its Wound specific decrease in Adult tissues through quantitative real-time RT-PCR assay. We also confirm that quantitative evaluation of CCT-alpha and CCT-zeta mRNA expression shows no change in healing fetal Wounds.
Eric J. Stelnicki - One of the best experts on this subject based on the ideXlab platform.
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Fetal Wound Repair: Where Do We Go From Here?
Seminars in pediatric surgery, 1999Co-Authors: Eric J. Stelnicki, Gyu S. Chin, George K. Gittes, Michael T. LongakerAbstract:In contrast to Adult Wound healing, early-gestation fetal skin Wound healing occurs rapidly, in a regenerative fashion, and without scar formation. The accelerated rate of healing, relative lack of an acute inflammatory response, and an absence of neovascularization distinguishes fetal from Adult Wound healing. However, this remarkable ability of the fetus to heal without scarring still remains poorly understood. The uncertainties include the role of cytokines, extracellular matrix components, homeobox genes, and certain cell types in the scarless Wound repair process. Nevertheless, some strides have been made within the last two decades. This report, discusses the current knowledge of the mechanisms and characteristics of scarless fetal Wound healing. Furthermore, to shy away from being just another all inclusive review, the authors point out deficiencies in the knowledge base on this important topic. Last, the future direction of research is discussed that may elucidate the mechanisms regulating the scarless repair phenomena.
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modulation of the human homeobox genes prx 2 and hoxb13 in scarless fetal Wounds
Journal of Investigative Dermatology, 1998Co-Authors: Eric J. Stelnicki, Michael R. Harrison, Darrell L. Cass, Jeff Arbeit, Catherine Saner, Corey LargmanAbstract:Scarless healing of cutaneous Wounds occurs in humans during the first two trimesters of development, but by birth all Wounds are repaired with scar formation. To search for transcriptional regulatory genes that might mediate fetal tissue regeneration, we surveyed homeobox gene expression in proliferating fetal fibroblasts and in Wounded and unWounded skin. Two novel human homeobox genes, PRX-2 and HOXB13, were identified that were differentially expressed during fetal versus Adult Wound healing. Both genes were predominantly expressed in proliferating fetal fibroblasts and developing dermis, and PRX-2 was downregulated in Adult skin. In a model of scarless fetal skin regeneration, PRX-2 expression was strongly increased compared with unWounded skin and the signal was localized to the Wounded dermis, the site of scarless repair. Conversely, in Adult skin weak epidermal PRX-2 expression was observed, mRNA levels were not increased by Wounding, and no dermal expression was detected. HOXB13 expression was decreased in Wounded fetal tissue relative to unWounded fetal controls or Wounded Adult skin. Thus both HOXB13 and PRX-2 are expressed in patterns consistent with roles in fetal skin development and cutaneous regeneration.
Latha Satish - One of the best experts on this subject based on the ideXlab platform.
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Scarless integumentary Wound healing in the mammalian fetus: Molecular basis and therapeutic implications
Birth defects research. Part C Embryo today : reviews, 2012Co-Authors: Sandeep Kathju, Phillip H. Gallo, Latha SatishAbstract:Adult mammals respond to injury of their skin/integument by forming scar tissue. Scar is useful in rapidly sealing an injured area, but can also lead to significant morbidity. Mammals in fetal life retain the ability to heal integumentary Wounds regeneratively, without scar. The critical molecular mechanisms governing this remarkable phenomenon have been a subject of great interest, in the hopes that these could be dissected and recapitulated in the healing Adult Wound, with the goal of inducing scarless healing in injured patients. Multiple lines of investigation spanning decades have implicated a number of factors in distinguishing scarless from fibrotic Wound healing, including most prominently transforming growth factor-β and interleukin-10, among others. Therapeutic interventions to try to mitigate scarring in Adult Wounds have been developed out of these studies, and have reached the level of clinical trials in humans, although as yet no FDA-approved treatment exists. More recent expressomic studies have revealed many more genes that are differentially expressed in scarlessly healing fetal Wounds compared with Adult, and microRNAs have also been identified as participating in the fetal Wound healing response. These represent an even greater range of potential therapeutics (or targets for therapy) to translate the promise of scarless fetal Wound healing to the injured Adult patient. Birth Defects Research (Part C) 96:223–236, 2012. © 2012 Wiley Periodicals, Inc.
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Cellular and Molecular Characteristics of Scarless versus Fibrotic Wound Healing
Dermatology research and practice, 2010Co-Authors: Latha Satish, Sandeep KathjuAbstract:The purpose of this paper is to compare and contrast the discrete biology differentiating fetal Wound repair from its Adult counterpart. Integumentary Wound healing in mammalian fetuses is essentially different from Wound healing in Adult skin. Adult (postnatal) skin Wound healing is a complex and well-orchestrated process spurred by attendant inflammation that leads to Wound closure with scar formation. In contrast, fetal Wound repair occurs with minimal inflammation, faster re-epithelialization, and without the accumulation of scar. Although research into scarless healing began decades ago, the critical molecular mechanisms driving the process of regenerative fetal healing remain uncertain. Understanding the molecular and cellular events during regenerative healing may provide clues that one day enable us to modulate Adult Wound healing and consequently reduce scarring.
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Cloning and expression of rabbit CCT subunits eta and beta in healing cutaneous Wounds
Cell Stress and Chaperones, 2010Co-Authors: Latha Satish, Sandra Johnson, Adam Abdulally, J. Christopher Post, Garth D. Ehrlich, Sandeep KathjuAbstract:We have previously identified the CCT subunit eta as specifically reduced in healing fetal skin Wounds by differential display, and observed that this reduction is not seen with any other CCT subunit. We now report the cloning and characterization of the cDNAs for rabbit CCT-eta and its closest evolutionary homolog, CCT-beta. Quantitative examination of CCT-eta and –beta message expression in healing fetal and Adult Wounds at 12 h post-injury confirms that CCT-eta mRNA is decreased in fetal Wound tissues, but actually elevated in Adult Wound tissues. CCT-beta mRNA, in contrast, remains unchanged in both fetal and Adult Wound tissues. CCT-eta mRNA remains persistently elevated in healing Adult Wounds for 28 days following injury, whereas CCT-beta mRNA remains invariant throughout. CCT-eta protein is similarly increased, whereas CCT-beta protein remains unchanged. -smooth muscle actin ( -SMA), a recognized substrate of CCT known to be important in integumentary Wound healing, was also measured over the course of Wound healing, and both mRNA and protein levels were elevated throughout the 28 days.
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differential expression of chaperonin containing t complex polypeptide cct subunits during fetal and Adult skin Wound healing
Cell Stress & Chaperones, 2008Co-Authors: Latha Satish, Sandra Johnson, Adam Abdulally, Garth D. Ehrlich, Duane Oswald, Christopher J Post, Sandeep KathjuAbstract:Integumentary Wound healing in early fetal life is regenerative and proceeds without scar formation. Expressomic analysis of this phenomenon by differential display has previously determined that the eta subunit of the cytosolic chaperonin containing T-complex polypeptide (CCT) is downregulated in the healing fetal Wound milieu. We now report that no other CCT subunit shares this distinct pattern of gene regulation as determined by limiting dilution reverse transcriptase polymerase chain reaction (RT-PCR); all seven of the remaining CCT subunits demonstrate no change in messenger RNA (mRNA) expression in healing fetal Wounds compared to unWounded control tissue. The alpha subunit, however, did evidence reduced message levels in healing Adult Wound tissue. We herein report on the cloning and sequence of the complementary DNA (cDNA) for rabbit CCT-alpha and confirm its Wound specific decrease in Adult tissues through quantitative real-time RT-PCR assay. We also confirm that quantitative evaluation of CCT-alpha and CCT-zeta mRNA expression shows no change in healing fetal Wounds.
