Pigment epithelium-derived factor short peptides facilitate full-thickness cutaneous wound healing by promoting epithelial basal cell and hair follicle stem cell proliferation

A previous study by our group showed that a 44-amino-acid fragment of pigment epithelium-derived factor (PEDF) facilitated corneal epithelial wound healing. In the present study this fragment was shortened to obtain peptides of 18, 20 and 29 amino acids in length, and their promoting effects on the healing of full-thickness skin wounds were assessed. Peptides were delivered periodically by topical application to punch wounds of mice. The wound healing speed was evaluated by measuring the reduction of wound areas at 4 and 7 days after injury. Histological analysis with Masson's trichrome staining was used to confirm epithelialization and dermal collagen deposition. Proliferation of epithelial basal cells was documented by 5-bromo-2′-deoxyuridine incorporation. Hair follicle stem cells were identified by immunostaining for leucine-rich repeat-containing G protein-coupled receptor 6. The results indicated that the 20- and 29-amino-acid short peptides significantly reduced the time required for wound healing compared to the vehicle. Histological analysis confirmed faster epithelial cell coverage of open wounds. Treatment with the PEDF peptide fragments also contributed to granulation, tissue formation by increasing the fibroblast population and enhancing collagen deposition in the dermis. Wounds treated with PEDF peptide fragments contained more basal cells proliferated in the epithelium. Moreover, hair follicle stem cells were also stimulated to proliferate by peptide exposure. In conclusion, the present study reported the identification of two short peptides that can enhance the healing of full-thickness skin wounds following topical application. The underlying mechanisms may involve activation of basal cell proliferation and mobilization of hair follicle stem cells.

[1]  Y. Tsao,et al.  PEDF-derived peptide promotes skeletal muscle regeneration through its mitogenic effect on muscle progenitor cells. , 2015, American journal of physiology. Cell physiology.

[2]  T. Zhou,et al.  High Levels of Pigment Epithelium–Derived Factor in Diabetes Impair Wound Healing Through Suppression of Wnt Signaling , 2014, Diabetes.

[3]  L. DiPietro,et al.  Production and function of pigment epithelium‐derived factor in isolated skin keratinocytes , 2014, Experimental dermatology.

[4]  Y. Tsao,et al.  PEDF promotes self‐renewal of limbal stem cell and accelerates corneal epithelial wound healing , 2013, Stem cells.

[5]  S. Yamagishi,et al.  PEDF-derived peptide inhibits corneal angiogenesis by suppressing VEGF expression. , 2012, Microvascular research.

[6]  O. Stojadinović,et al.  Hair cycling and wound healing: to pluck or not to pluck? , 2011, The Journal of investigative dermatology.

[7]  H. Clevers,et al.  Lgr6 Marks Stem Cells in the Hair Follicle That Generate All Cell Lineages of the Skin , 2010, Science.

[8]  V. Marigo,et al.  PEDF promotes retinal neurosphere formation and expansion in vitro. , 2010, Advances in experimental medicine and biology.

[9]  A. Bayat,et al.  Exploring the role of stem cells in cutaneous wound healing , 2009, Experimental dermatology.

[10]  U. Schlötzer-Schrehardt,et al.  Corneal Limbal Microenvironment Can Induce Transdifferentiation of Hair Follicle Stem Cells into Corneal Epithelial-like Cells , 2009, Stem cells.

[11]  Harshini Sarojini,et al.  PEDF from mouse mesenchymal stem cell secretome attracts fibroblasts , 2008, Journal of cellular biochemistry.

[12]  G. Cotsarelis,et al.  Is the hair follicle necessary for normal wound healing? , 2008, The Journal of investigative dermatology.

[13]  Sabine Werner,et al.  Keratinocyte-fibroblast interactions in wound healing. , 2007, The Journal of investigative dermatology.

[14]  D. Steed Clinical Evaluation of Recombinant Human Platelet-Derived Growth Factor for the Treatment of Lower Extremity Ulcers , 2006, Plastic and reconstructive surgery.

[15]  I. Fariñas,et al.  Pigment epithelium–derived factor is a niche signal for neural stem cell renewal , 2006, Nature Neuroscience.

[16]  W. Jiang,et al.  Pigment Epithelium-derived Factor Inhibits Angiogenesis via Regulated Intracellular Proteolysis of Vascular Endothelial Growth Factor Receptor 1* , 2006, Journal of Biological Chemistry.

[17]  M. Ponec,et al.  Role of fibroblasts in the regulation of proinflammatory interleukin IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1 , 1996, Archives of Dermatological Research.

[18]  Jane Q. Nguyen,et al.  Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis , 2005, Nature Medicine.

[19]  Emelyn H. Shroff,et al.  Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer. , 2005, Cancer research.

[20]  S. Werner,et al.  Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts , 2005, Journal of Cell Science.

[21]  J. Enghild,et al.  Pigment-epithelium-derived factor (PEDF) occurs at a physiologically relevant concentration in human blood: purification and characterization. , 2003, The Biochemical journal.

[22]  S. Werner,et al.  Regulation of wound healing by growth factors and cytokines. , 2003, Physiological reviews.

[23]  R. Gamelli,et al.  The effect of thrombocytopenia on dermal wound healing. , 2003, The Journal of investigative dermatology.

[24]  M. Willis,et al.  The cost-effectiveness of treating diabetic lower extremity ulcers with becaplermin (Regranex): a core model with an application using Swedish cost data. , 2000, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[25]  A. Wysocki Wound Fluids and the Pathogenesis of Chronic Wounds , 1996, Journal of wound, ostomy, and continence nursing : official publication of The Wound, Ostomy and Continence Nurses Society.

[26]  K. J. Stewart,et al.  A quantitative ultrastructural study of collagen fibrils in human skin normal scars, and hypertrophic scars , 1995, Clinical anatomy.

[27]  N. Fusenig,et al.  Mutual induction of growth factor gene expression by epidermal-dermal cell interaction , 1993, The Journal of cell biology.

[28]  E. Waelti,et al.  Co-culture of human keratinocytes on post-mitotic human dermal fibroblast feeder cells: production of large amounts of interleukin 6. , 1992, The Journal of investigative dermatology.