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Epidermal or Dermal Specific Knockout of PHD-2 Enhances Wound Healing and Minimizes Ischemic Injury  [PDF]
Andrew S. Zimmermann, Shane D. Morrison, Michael S. Hu, Shuli Li, Allison Nauta, Michael Sorkin, Nathaniel P. Meyer, Graham G. Walmsley, Zeshaan N. Maan, Denise A. Chan, Geoffrey C. Gurtner, Amato J. Giaccia, Michael T. Longaker
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093373
Abstract: Introduction Hypoxia-inducible factor (HIF)-1α, part of the heterodimeric transcription factor that mediates the cellular response to hypoxia, is critical for the expression of multiple angiogenic growth factors, cell motility, and the recruitment of endothelial progenitor cells. Inhibition of the oxygen-dependent negative regulator of HIF-1α, prolyl hydroxylase domain-2 (PHD-2), leads to increased HIF-1α and mimics various cellular and physiological responses to hypoxia. The roles of PHD-2 in the epidermis and dermis have not been clearly defined in wound healing. Methods Epidermal and dermal specific PHD-2 knockout (KO) mice were developed in a C57BL/6J (wild type) background by crossing homozygous floxed PHD-2 mice with heterozygous K14-Cre mice and heterozygous Col1A2-Cre-ER mice to get homozygous floxed PHD-2/heterozygous K14-Cre and homozygous floxed PHD-2/heterozygous floxed Col1A2-Cre-ER mice, respectively. Ten to twelve-week-old PHD-2 KO and wild type (WT) mice were subjected to wounding and ischemic pedicle flap model. The amount of healing was grossly quantified with ImageJ software. Western blot and qRT-PCR was run on protein and RNA from primary cells cultured in vitro. Results qRT-PCR demonstrated a significant decrease of PHD-2 in keratinocytes and fibroblasts derived from tissue specific KO mice relative to control mice (*p<0.05). Western blot analysis showed a significant increase in HIF-1α and VEGF protein levels in PHD-2 KO mice relative to control mice (*p<0.05). PHD-2 KO mice showed significantly accelerated wound closure relative to WT (*p<0.05). When ischemia was analyzed at day nine post-surgery in a flap model, the PHD-2 tissue specific knockout mice showed significantly more viable flaps than WT (*p<0.05). Conclusions PHD-2 plays a significant role in the rates of wound healing and response to ischemic insult in mice. Further exploration shows PHD-2 KO increases cellular levels of HIF-1α and this increase leads to the transcription of downstream angiogenic factors such as VEGF.
Spreading speeds and traveling waves for a model of epidermal wound healing  [PDF]
Haiyan Wang
Quantitative Biology , 2010,
Abstract: In this paper, we shall establish the spreading speed and existence of traveling waves for a non-cooperative system arising from epidermal wound healing and characterize the spreading speed as the slowest speed of a family of non-constant traveling wave solutions. Our results on the spreading speed and traveling waves can also be applied to a large class of non-cooperative reaction-diffusion systems.
Epidermal wound healing in severe sepsis and septic shock in humans
Marjo Koskela, Fiia G?ddn?s, Tero I Ala-Kokko, Jouko J Laurila, Juha Saarnio, Aarne Oikarinen, Vesa Koivukangas
Critical Care , 2009, DOI: 10.1186/cc7932
Abstract: Blister wounds were induced in 35 patients with severe sepsis and in 15 healthy controls. The healing of the wounds was followed up by measuring transepidermal water loss and blood flow in the wound, reflecting the restoration of the epidermal barrier function and inflammation, respectively. The first set of suction blisters (early wound) was made within 48 hours of the first sepsis-induced organ failure and the second set (late wound) four days after the first wound. In addition, measurements were made on the intact skin.The average age of the whole study population was 62 years (standard deviation [SD] 12). The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission was 25 (SD 8). The two most common causes of infections were peritonitis and pneumonia. Sixty-six percent of the patients developed multiple organ failure. The decrease in water evaporation from the wound during the first four days was lower in septic patients than in the control subjects (56 g/m2 per hour versus 124 g/m2 per hour, P = 0.004). On the fourth day, septic patients had significantly higher blood flow in the wound compared with the control subjects (septic patients 110 units versus control subjects 47 units, P = 0.001). No difference in transepidermal water loss from the intact skin was found between septic patients and controls. Septic patients had higher blood flow in the intact skin on the fourth and on the eighth day of study compared with the controls.The restoration of the epidermal barrier function is delayed and wound blood flow is increased in patients with severe sepsis.Sepsis and systemic inflammatory response syndrome have been assumed to disturb epidermal barrier function and wound healing [1-3]. Sepsis has profound effects on the maintenance of epithelial barriers: the barriers of gut and gall bladder, which are essential to homeostasis and innate immune function, have been shown to be disturbed by sepsis and multiple organ dysfunction syndrome [3
ROCK Inhibitor Enhances Adhesion and Wound Healing of Human Corneal Endothelial Cells  [PDF]
Aurélien Pipparelli, Yvan Arsenijevic, Gilles Thuret, Philippe Gain, Michael Nicolas, Fran?ois Majo
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062095
Abstract: Maintenance of corneal transparency is crucial for vision and depends mainly on the endothelium, a non-proliferative monolayer of cells covering the inner part of the cornea. When endothelial cell density falls below a critical threshold, the barrier and “pump” functions of the endothelium are compromised which results in corneal oedema and loss of visual acuity. The conventional treatment for such severe disorder is corneal graft. Unfortunately, there is a worldwide shortage of donor corneas, necessitating amelioration of tissue survival and storage after harvesting. Recently it was reported that the ROCK inhibitor Y-27632 promotes adhesion, inhibits apoptosis, increases the number of proliferating monkey corneal endothelial cells in vitro and enhance corneal endothelial wound healing both in vitro and in vivo in animal models. Using organ culture human cornea (N = 34), the effect of ROCK inhibitor was evaluated in vitro and ex vivo. Toxicity, corneal endothelial cell density, cell proliferation, apoptosis, cell morphometry, adhesion and wound healing process were evaluated by live/dead assay standard cell counting method, EdU labelling, Ki67, Caspase3, Zo-1 and Actin immunostaining. We demonstrated for the first time in human corneal endothelial cells ex vivo and in vitro, that ROCK inhibitor did not induce any toxicity effect and did not alter cell viability. ROCK inhibitor treatment did not induce human corneal endothelial cells proliferation. However, ROCK inhibitor significantly enhanced adhesion and wound healing. The present study shows that the selective ROCK inhibitor Y-27632 has no effect on human corneal endothelial cells proliferative capacities, but alters cellular behaviours. It induces changes in cell shape, increases cell adhesion and enhances wound healing ex vivo and in vitro. Its absence of toxicity, as demonstrated herein, is relevant for its use in human therapy.
Valproic Acid Induces Cutaneous Wound Healing In Vivo and Enhances Keratinocyte Motility  [PDF]
Soung-Hoon Lee,Muhammad Zahoor,Jae-Kwan Hwang,Do Sik Min,Kang-Yell Choi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048791
Abstract: Cutaneous wound healing is a complex process involving several signaling pathways such as the Wnt and extracellular signal-regulated kinase (ERK) signaling pathways. Valproic acid (VPA) is a commonly used antiepileptic drug that acts on these signaling pathways; however, the effect of VPA on cutaneous wound healing is unknown.
Antimycotic Ciclopirox Olamine in the Diabetic Environment Promotes Angiogenesis and Enhances Wound Healing  [PDF]
Sae Hee Ko, Allison Nauta, Shane D. Morrison, Hongyan Zhou, Andrew Zimmermann, Geoffrey C. Gurtner, Sheng Ding, Michael T. Longaker
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027844
Abstract: Diabetic wounds remain a major medical challenge with often disappointing outcomes despite the best available care. An impaired response to tissue hypoxia and insufficient angiogenesis are major factors responsible for poor healing in diabetic wounds. Here we show that the antimycotic drug ciclopirox olamine (CPX) can induce therapeutic angiogenesis in diabetic wounds. Treatment with CPX in vitro led to upregulation of multiple angiogenic genes and increased availability of HIF-1α. Using an excisional wound splinting model in diabetic mice, we showed that serial topical treatment with CPX enhanced wound healing compared to vehicle control treatment, with significantly accelerated wound closure, increased angiogenesis, and increased dermal cellularity. These findings offer a promising new topical pharmacologic therapy for the treatment of diabetic wounds.
Secretome of Peripheral Blood Mononuclear Cells Enhances Wound Healing  [PDF]
Michael Mildner, Stefan Hacker, Thomas Haider, Maria Gschwandtner, Gregor Werba, Caterina Barresi, Matthias Zimmermann, Bahar Golabi, Erwin Tschachler, Hendrik Jan Ankersmit
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060103
Abstract: Non-healing skin ulcers are often resistant to most common therapies. Treatment with growth factors has been demonstrated to improve closure of chronic wounds. Here we investigate whether lyophilized culture supernatant of freshly isolated peripheral blood mononuclear cells (PBMC) is able to enhance wound healing. PBMC from healthy human individuals were prepared and cultured for 24 hours. Supernatants were collected, dialyzed and lyophilized (SECPBMC). Six mm punch biopsy wounds were set on the backs of C57BL/6J-mice and SECPBMC containing emulsion or controls were applied daily for three days. Morphology and neo-angiogenesis were analyzed by H&E-staining and CD31 immuno-staining, respectively. In vitro effects on diverse skin cells were investigated by migration assays, cell cycle analysis, and tube formation assay. Signaling pathways were analyzed by Western blot analysis. Application of SECPBMC on 6 mm punch biopsy wounds significantly enhanced wound closure. H&E staining of the wounds after 6 days revealed that wound healing was more advanced after application of SECPBMC containing emulsion. Furthermore, there was a massive increase in CD31 positive cells, indicating enhanced neo-angiogenesis. In primary human fibroblasts (FB) and keratinocytes (KC) migration but not proliferation was induced. In endothelial cells (EC) SECPBMC induced proliferation and tube-formation in a matrigel-assay. In addition, SECPBMC treatment of skin cells led to the induction of multiple signaling pathways involved in cell migration, proliferation and survival. In summary, we could show that emulsions containing the secretome of PBMC derived from healthy individuals accelerates wound healing in a mouse model and induce wound healing associated mechanisms in human primary skin cells. The formulation and use of such emulsions might therefore represent a possible novel option for the treatment of non-healing skin ulcers.
Whey protein enhances normal inflammatory responses during cutaneous wound healing in diabetic rats
Hossam Ebaid, Amir Salem, Abdalla Sayed, Ali Metwalli
Lipids in Health and Disease , 2011, DOI: 10.1186/1476-511x-10-235
Abstract: Whey protein was found to significantly decrease the levels of malondialdehyde (MDA), nitric oxide (NO) and ROS. A significant restoration of the glutathione level was observed in WDWP rats. During the early wound healing stage, IL-1β, TNF-α, IL-6, IL-4 and neutrophil infiltration were significantly decreased in WD mice. WP supplementation was found to restore the levels of these inflammatory markers to the levels observed in control animals. In addition, the time required for wound healing was significantly prolonged in diabetic rats. WP was found to significantly decrease the time required for wound healing in WDWP rats.In conclusion, dietary supplementation with WP enhances the normal inflammatory responses during wound healing in diabetic mice by restoring the levels of oxidative stress and inflammatory cytokines.The ability of animals to repair wounds is critical for survival after injury [1]. A multitude of cellular events, such as cell proliferation, cell migration, contraction and extracellular matrix degradation and synthesis, must occur to achieve wound closure and regeneration of the injured dermis [2]. These events rely on the temporal expression and activation of a variety of proteins, such as growth factors, cytokines and matrix metalloproteinases [3].Wound healing is initiated by an inflammatory phase that is followed by a proliferation phase, particularly the proliferation of fibroblasts and endothelial cells. The last phase involves the production and reorganization of the extracellular matrix, leading to repair or regeneration. The inflammatory phase leads to the recruitment of leukocytes that produce growth factors and remove debris from the wound [4-7]. The healing process requires an interaction between inflammatory cells and biochemical mediators, which is stimulated by a number of mitogens and chemotactic factors [4].The generation of oxygen radicals is normally balanced by the presence of adequate endogenous antioxidant defenses [8]. Oxidativ
Loss of the Desmosomal Component Perp Impairs Wound Healing In Vivo  [PDF]
Veronica G. Beaudry,Rebecca A. Ihrie,Suzanne B. R. Jacobs,Bichchau Nguyen,Navneeta Pathak,Eunice Park,Laura D. Attardi
Dermatology Research and Practice , 2010, DOI: 10.1155/2010/759731
Abstract: Epithelial wound closure is a complex biological process that relies on the concerted action of activated keratinocytes and dermal fibroblasts to resurface and close the exposed wound. Modulation of cell-cell adhesion junctions is thought to facilitate cellular proliferation and migration of keratinocytes across the wound. In particular, desmosomes, adhesion complexes critical for maintaining epithelial integrity, are downregulated at the wound edge. It is unclear, however, how compromised desmosomal adhesion would affect wound reepithelialization, given the need for a delicate balance between downmodulating adhesive strength to permit changes in cellular morphology and maintaining adhesion to allow coordinated migration of keratinocyte sheets. Here, we explore the contribution of desmosomal adhesion to wound healing using mice deficient for the desmosomal component Perp. We find that Perp conditional knockout mice display delayed wound healing relative to controls. Furthermore, we determine that while loss of Perp compromises cell-cell adhesion, it does not impair keratinocyte proliferation and actually enhances keratinocyte migration in in vitro assays. Thus, Perp's role in promoting cell adhesion is essential for wound closure. Together, these studies suggest a role for desmosomal adhesion in efficient wound healing. 1. Introduction A fundamental aspect of the skin’s ability to maintain barrier function is its rapid response to wounding. Critical components of adult wound healing include the contraction of the dermal tissue beneath the wound, which helps draw the wound edges in proximity, and reepithelialization, in which keratinocytes become activated to proliferate and migrate as an invading sheet to resurface the wound [1–3]. Keratinocytes display a number of distinct characteristics during wound healing, including increased size, elongated polarized morphology, compromised cell-cell adhesion, and retracted keratin filaments [2, 4, 5]. In addition, they undergo enhanced proliferation several cell diameters away from the wound edge [1, 3, 6]. These changes are thought to reflect reprogramming of epidermal keratinocytes to ones dedicated to wound healing. The dynamic regulation of cell-cell adhesion junctions, including desmosomes, is thought to be an important facet of wound healing. Desmosomal adhesion junctions are initially destabilized at the wound front, presumably to facilitate proliferation and migration, and are reassembled later during the sealing of the epithelium [7, 8]. Desmosomes are multiprotein cell-cell adhesion complexes essential
Somatostatin Inhibits Cell Migration and Reduces Cell Counts of Human Keratinocytes and Delays Epidermal Wound Healing in an Ex Vivo Wound Model  [PDF]
Matthias Vockel,Simone Pollok,Ute Breitenbach,Ina Ridderbusch,Hans-Jürgen Kreienkamp,Johanna M. Brandner
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019740
Abstract: The peptide hormone somatostatin (SST) and its five G protein-coupled receptors (SSTR1-5) were described to be present in the skin, but their cutaneous function(s) and skin-specific signalling mechanisms are widely unknown. By using receptor specific agonists we show here that the SSTRs expressed in keratinocytes are functionally coupled to the inhibition of adenylate cyclase. In addition, treatment with SSTR4 and SSTR5/1 specific agonists significantly influences the MAP kinase signalling pathway. As epidermal hormone receptors in general are known to regulate re-epithelialization following skin injury, we investigated the effect of SST on cell counts and migration of human keratinocytes. Our results demonstrate a significant inhibition of cell migration and reduction of cell counts by SST. We do not observe an effect on apoptosis and necrosis. Analysis of signalling pathways showed that somatostatin inhibits cell migration independent of its effect on cAMP. Migrating keratinocytes treated with SST show altered cytoskeleton dynamics with delayed lamellipodia formation. Furthermore, the activity of the small GTPase Rac1 is diminished, providing evidence for the control of the actin cytoskeleton by somatostatin receptors in keratinocytes. While activation of all receptors leads to redundant effects on cell migration, only treatment with a SSTR5/1 specific agonist resulted in decreased cell counts. In accordance with reduced cell counts and impaired migration we observe delayed re-epithelialization in an ex vivo wound healing model. Consequently, our experiments suggest SST as a negative regulator of epidermal wound healing.
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