Abstract
The authors have previously demonstrated that one phage-displayed keratinocyte growth factor (KGF) model peptide that can bind to epidermal cells and facilitate cellular proliferation. In this study, the authors investigated the role of phage-displayed KGF model peptide on wound healing in diabetic rats. Full-thickness excisional dorsal wounds were created in the diabetic rats, after which the rats were randomly divided into five groups: negative control group [normal saline (NS)], two KGF control groups which were respectively treated with low-dose KGF (5 ng/mL, K-LD) and high-dose KGF (50 ng/mL, K-HD), and two KGF model-peptide-treated groups which were respectively treated with low-dose model peptide (5 ng/mL, M-LD) and high-dose model peptide (50 ng/mL, M-HD). On day 14 post-injury, wound closure was followed by digital planimetry and wound tissues were harvested for histologic assay and real-time polymerase chain reaction. Wounds treated with model peptide closed markedly faster than negative control wounds and were comparable to KGF treated wounds. Histology and immunohistology results demonstrated significantly higher levels of re-epithelization, granulation tissue formation and vascularization in the model peptide groups. Furthermore, real-time polymerase chain reaction expression of KGFR, collagen I and transforming growth factor-β1 in model peptide groups, were also generally higher than that in negative control group. Phage-displayed KGF peptide promotes wound healing through accelerating re-epithelialization, enhancing dermal regeneration, and inducing angiogenesis. Model peptide possesses the potential to be a promising therapeutic option for the treatment of diabetic ulcers.
Similar content being viewed by others
References
Bitar MS (2019) Diabetes impairs angiogenesis and induces endothelial cell senescence by up-regulating thrombospondin-CD47-dependent signaling. Int J Mol Sci 20:673
Brown LF, Yeo KT, Berse B, Yeo TK, Senger DR, Dvorak HF et al (1992) Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med 176:1375–1379
Coffey RJ, Derynck R, Wilcox JN, Bringman TS, Goustin AS, Moses HL et al (1987) Production and auto-induction of transforming growth factor-alpha in human keratinocytes. Nature 328:817–820
Danilenko DM, Ring BD, Yanagihara D, Benson W, Wiemann B, Starnes CO et al (1995) Keratinocyte growth factor is an important endogenous mediator of hair follicle growth, development, and differentiation. Normalization of the nu/nu follicular differentiation defect and amelioration of chemotherapy-induced alopecia. Am J Pathol 147:145–154
de Giorgi V, Sestini S, Massi D, Ghersetich I, Lotti T (2007) Keratinocyte growth factor receptors. Dermatol Clin 25:477–485
Del GC, Baiguera S, Boieri M, Mazzanti B, Ribatti D, Bianco A et al (2013) Induction of angiogenesis using VEGF releasing genipin-crosslinked electrospun gelatin mats. Biomaterials 34:7754–7765
Devalliere J, Dooley K, Hu Y, Kelangi SS, Uygun BE, Yarmush ML (2017) Co-delivery of a growth factor and a tissue-protective molecule using elastin biopolymers accelerates wound healing in diabetic mice. Biomaterials 141:149–160
He M, Han T, Wang Y, Wu YH, Qin WS, Du LZ et al (2019) Effects of HGF and KGF gene silencing on vascular endothelial growth factor and its receptors in rat ultraviolet radiation-induced corneal neovascularization. Int J Mol Med 43:1888–1899
Hirobe T, Shibata T, Fujiwara R, Sato K (2016) Platelet-derived growth factor regulates the proliferation and differentiation of human melanocytes in a differentiation-stage-specific manner. J Dermatol Sci 83:200–209
Ishii T, Uchida K, Hata S, Hatta M, Kita T, Miyake Y et al (2018) TRPV2 channel inhibitors attenuate fibroblast differentiation and contraction mediated by keratinocyte-derived TGF-β1 in an in vitro wound healing model of rats. J Dermatol Sci 90:332–342
Jeon HH, Yu Q, Lu Y, Spencer E, Lu C, Milovanova T et al (2018) FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds. J Pathol 245:258–264
Jettanacheawchankit S, Sasithanasate S, Sangvanich P, Banlunara W, Thunyakitpisal P (2009) Acemannan stimulates gingival fibroblast proliferation; expressions of keratinocyte growth factor-1, vascular endothelial growth factor, and type I collagen; and wound healing. J Pharmacol Sci 109:525–531
Li Y, Liu M, Xie S (2020) Harnessing phage display for the discovery of peptide-based drugs and monoclonal antibodies. Curr Med Chem
Marti G, Ferguson M, Wang J, Byrnes C, Dieb R, Qaiser R et al (2004) Electroporative transfection with KGF-1 DNA improves wound healing in a diabetic mouse model. Gene Ther 11:1780–1785
Meyer M, Müller A, Yang J, Moik D, Ponzio G, Ornitz DM et al (2012) FGF receptors 1 and 2 are key regulators of keratinocyte migration in vitro and in wounded skin. J Cell Sci 125:5690–5701
Miki T, Fleming TP, Bottaro DP, Rubin JS, Ron D, Aaronson SA (1991) Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop. Science 251:72–75
Milan PB, Lotfibakhshaiesh N, Joghataie MT, Ai J, Pazouki A, Kaplan DL et al (2016) Accelerated wound healing in a diabetic rat model using decellularized dermal matrix and human umbilical cord perivascular cells. Acta Biomater 45:234–246
Mohd AM, Sum JS, Aminuddin BN, Choong YS, Nor AN, Amran F et al (2020) Development of monoclonal antibodies against recombinant LipL21 protein of pathogenic Leptospira through phage display technology. Int J Biol Macromol 168:289–300
Peng C, He Q, Luo C (2011) Lack of keratinocyte growth factor retards angiogenesis in cutaneous wounds. J Int Med Res 39:416–423
Peng Y, Wu S, Tang Q, Li S, Peng C (2019) KGF-1 accelerates wound contraction through the TGF-β1/Smad signaling pathway in a double-paracrine manner. J Biol Chem 294:8361–8370
Pierce GF, Yanagihara D, Klopchin K, Danilenko DM, Hsu E, Kenney WC et al (1994) Stimulation of all epithelial elements during skin regeneration by keratinocyte growth factor. J Exp Med 179:831–840
Saw PE, Song EW (2019) Phage display screening of therapeutic peptide for cancer targeting and therapy. Protein Cell 10:787–807
Sawada T, Oyama R, Tanaka M, Serizawa T (2020) Discovery of surfactant-like peptides from a phage-displayed peptide library. Viruses 12:1442
Shirakata Y, Kimura R, Nanba D, Iwamoto R, Tokumaru S, Morimoto C et al (2005) Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing. J Cell Sci 118:2363–2370
Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341:738–746
Staiano-Coico L, Krueger JG, Rubin JS, D’Limi S, Vallat VP, Valentino L et al (1993) Human keratinocyte growth factor effects in a porcine model of epidermal wound healing. J Exp Med 178:865–878
Wang X, Yu M, Zhu W, Bao T, Zhu L, Zhao W et al (2013) Adenovirus-mediated expression of keratinocyte growth factor promotes secondary flap necrotic wound healing in an extended animal model. Aesthetic Plast Surg 37:1023–1033
Werner S, Peters KG, Longaker MT, Fuller-Pace F, Banda MJ, Williams LT (1992) Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci USA 89:6896–6900
Werner S, Breeden M, Hübner G, Greenhalgh DG, Longaker MT (1994) Induction of keratinocyte growth factor expression is reduced and delayed during wound healing in the genetically diabetic mouse. J Invest Dermatol 103:469–473
Wu L, Pierce GF, Galiano RD, Mustoe TA (1996) Keratinocyte growth factor induces granulation tissue in ischemic dermal wounds. Importance of epithelial-mesenchymal cell interactions. Arch Surg 131:660–666
Yu P, Jiang D, Song G, Lu H, Zong X, Jin X (2020) Phage-displayed peptide of keratinocyte growth factor and its biological effects on epidermal cells. Int J Pept Res Ther 26:661–666
Zhang D, Huang J, Li W, Zhang Z, Zhu M, Feng Y et al (2020) Screening and identification of a CD44v6 specific peptide using improved phage display for gastric cancer targeting. Ann Transl Med 8:1442
Acknowledgements
This study was supported by the National Natural Science Foundation of China (30670571, 81201467), and the Scientific Research Fund for Youth of Chinese Academy of Medical Sciences and Peking Union Medical College (2017310007).
Funding
This study was supported by the National Natural Science Foundation of China (30670571, 81201467), and the Scientific Research Fund for Youth of Chinese Academy of Medical Sciences and Peking Union Medical College (2017310007).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that there are no conflicts of interest.
Ethical Approval
The current research was approved by the Medical Ethical Committee at Plastic Surgery Hospital of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Informed Consent
In this type of study, formal consent is not required.
Research Involving Human and/or Animal Participants
50 female Sprague–Dawley (SD) rats were obtained from Beijing Medical Laboratory Animal Center (SYXK 2020–0018). This article does not contain any studies with human participants performed by any of the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Du, H., Song, G., Cao, C. et al. KGF Phage Model Peptide Accelerates Cutaneous Wound Healing in a Diabetic Rat Model. Int J Pept Res Ther 27, 1769–1781 (2021). https://doi.org/10.1007/s10989-021-10209-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10989-021-10209-9