We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

EGFL7 affects the migration of epidermal stem cells in refractory diabetic wounds by regulating Notch signaling pathway

    Jinyuan Chang

    Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China

    ,
    Yang Sun

    Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China

    ,
    Xianxi Meng

    Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China

    ,
    Fanglin Zeng

    Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China

    &
    Xiancheng Wang

    *Author for correspondence:

    E-mail Address: wangxiancheng_wxc1@163.com

    Department of Burn and Plastic Surgery, The Second Xiangya Hospital of Central South University, No. 139, Shaoshan South Road, Furong District, Changsha, Hunan, 410011, China

    Published Online:https://doi.org/10.2217/rme-2022-0123

    Aim: This study aimed to explore the role of EGFL7 in the healing process of refractory diabetic wounds. Methods: Epidermal stem cells (ESCs) were isolated from healthy mice and diabetic mice, identified by immunofluorescence, transfected with EGFL7 overexpression and silencing lentiviral vectors, and treated with Notch pathway inhibitor (DAPT). Results: SiEGFL7 significantly inhibited the proliferation, invasion and migration of ESCs of healthy mice. DAPT prominently inhibited the expressions of Notch1, Notch2, Hes1 and Jag1 in ESCs of healthy mice induced by overexpressed EGFL7. Overexpressed EGFL7 promoted wound healing in diabetic mice with refractory wounds. Conclusion: EGFL7 affects the proliferation and migration of ESCs in refractory diabetic wounds by regulating the Notch signaling pathway.

    Plain language summary

    EGFL7 silencing inhibited the proliferation, invasion and migration of ESCs of healthy mice, which was reversed by Notch signaling inhibition. Overexpressed EGFL7 promoted wound healing in diabetic mice with refractory wounds, providing a promising potential for the treatment of diabetic wound.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Ambrozova N, Ulrichova J, Galandakova A. Models for the study of skin wound healing. The role of Nrf2 and NF-kappaB. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 161(1), 1–13 (2017).
    • 2. Faries PL, Teodorescu VJ, Morrissey NJ et al. The role of surgical revascularization in the management of diabetic foot wounds. Am. J. Surg. 187(5a), 34S–37S (2004).
    • 3. Papaioannou D, Shen C, Nicolet D et al. Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia. Proc. Natl Acad. Sci. USA 114(23), E4641–E4647 (2017).
    • 4. Lian Z, Yin X, Li H et al. Synergistic effect of bone marrow-derived mesenchymal stem cells and platelet-rich plasma in streptozotocin-induced diabetic rats. Ann. Dermatol. 26(1), 1–10 (2014).
    • 5. Ramanujam CL, Facaros Z, Zgonis T. External fixation for surgical off-loading of diabetic soft tissue reconstruction. Clin. Podiatr. Med. Surg. 28(1), 211–216 (2011).
    • 6. Yang RH, Qi SH, Ruan SB et al. EGFL7-overexpressing epidermal stem cells promotes fibroblast proliferation and migration via mediating cell adhesion and strengthening cytoskeleton. Mol. Cell. Biochem. 423(1-2), 1–8 (2016). • Describes that overexpression of EGFL7 in epidermal stem cells improves the migration and proliferation abilities of cells, which is conducive to wound healing.
    • 7. Finley PJ, DeClue CE, Sell SA et al. Diabetic Wounds Exhibit Decreased Ym1 and Arginase Expression with Increased Expression of IL-17 and IL-20. Adv. Wound Care (New Rochelle) 5(11), 486–494 (2016).
    • 8. Luan A, Hu MS, Leavitt T et al. Noncoding RNAs in wound healing: a new and vast frontier. Adv. Wound Care (New Rochelle). 7(1), 19–27 (2018).
    • 9. Ran LW, Wang H, Lan D et al. Effect of RNA interference targeting gene combined with ultrasonic irradiation and sonovue microbubbles on proliferation and apoptosis in keratinocytes of psoriatic lesions. Chin. Med. J. 131(17), 2097–2104 (2018).
    • 10. Laiva AL, O'Brien FJ, Keogh MB. Innovations in gene and growth factor delivery systems for diabetic wound healing. J.Tissue Eng. Regen. Med. 12(1), e296–e312 (2018).
    • 11. Dwivedi C, Pandey I, Pandey H et al. In vivo diabetic wound healing with nanofibrous scaffolds modified with gentamicin and recombinant human epidermal growth factor. J. Biomed. Mater. Res. A. 106(3), 641–651 (2018).
    • 12. Sato H, Ebisawa K, Takanari K et al. Skin-derived precursor cells promote wound healing in diabetic mice. Ann. Plast. Surg. 74(1), 114–120 (2015).
    • 13. Maranda EL, Rodriguez-Menocal L, Badiavas EV. Role of mesenchymal stem cells in dermal repair in burns and diabetic wounds. Curr. Stem Cell Res. Ther. 12(1), 61–70 (2017).
    • 14. Liu Q, Wang J, Yang H et al. Attenuation of EGFL7 expression inhibits growth hormone-producing pituitary adenomas growth and invasion. Hum. Gene Ther. doi:10.1089/hum.2017.200 (2018).
    • 15. Motlik J, Klima J, Dvorankova B et al. Porcine epidermal stem cells as a biomedical model for wound healing and normal/malignant epithelial cell propagation. Theriogenology. 67(1), 105–111 (2007).
    • 16. Lataillade JJ, Magne B, Bey E et al. [Skin engineering for severe burns]. Transfus. Clin. Biol. 24(3), 245–250 (2017).
    • 17. Zarei F, Soleimaninejad M. Role of growth factors and biomaterials in wound healing. Artif. Cells Nanomed. Biotechnol. 46(Suppl. 1), 906–911 (2018).
    • 18. Haalboom M. Chronic Wounds: Innovations in Diagnostics and Therapeutics. Curr. Med. Chem. 25(41), 5772–5781 (2018).
    • 19. Brem H, Golinko MS, Stojadinovic O et al. Primary cultured fibroblasts derived from patients with chronic wounds: a methodology to produce human cell lines and test putative growth factor therapy such as GMCSF. J. Transl. Med. 6, 75 (2008).
    • 20. Li Z, Ni CF, Zhou J et al. Expression of epidermal growth factor-like domain 7 is increased by transcatheter arterial embolization of liver tumors. Asian Pac. J. Cancer Prev. 16(3), 1191–1196 (2015).
    • 21. Schmidt M, Paes K, De Maziere A et al. EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution. Development 134(16), 2913–2923 (2007).
    • 22. Steinbuck MP, Arakcheeva K, Winandy S. Novel TCR-Mediated Mechanisms of Notch Activation and Signaling. J. Immunol. 200(3), 997–1007 (2018).
    • 23. Sawangarun W, Mandasari M, Aida J et al. Loss of Notch1 predisposes oro-esophageal epithelium to tumorigenesis. Exp. Cell Res. 372(2), 129–140 (2018).
    • 24. Zhou JX, Han JB, Chen SM et al. γ-secretase inhibition combined with cisplatin enhances apoptosis of nasopharyngeal carcinoma cells. Exp. Ther. Med. 3(2), 357–361 (2012). • Describes γ-secretase inhibition.
    • 25. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4), 402–408 (2001).
    • 26. Hu MH, Ma CY, Wang XM et al. MicroRNA-126 inhibits tumor proliferation and angiogenesis of hepatocellular carcinoma by down-regulating EGFL7 expression. Oncotarget 7(41), 66922–66934 (2016).
    • 27. Deng QJ, Xie LQ, Li H. Overexpressed MALAT1 promotes invasion and metastasis of gastric cancer cells via increasing EGFL7 expression. Life Sci. 157, 38–44 (2016).
    • 28. Lu S, Dong W, Zhao P et al. lncRNA FAM83H-AS1 is associated with the prognosis of colorectal carcinoma and promotes cell proliferation by targeting the Notch signaling pathway. Oncol. Lett. 15(2), 1861–1868 (2018).
    • 29. Shin VY, Siu MT, Liu X et al. MiR-92 suppresses proliferation and induces apoptosis by targeting EP4/Notch1 axis in gastric cancer. Oncotarget. 9(36), 24209–24220 (2018).
    • 30. Ding W, Zeng T, Tao W et al. Effect of lenalidomide on the human gastric cancer cell line SGC7901/vincristine Notch signaling. J. Cancer Res. Ther. 14(Suppl.), S237–S242 (2018).
    • 31. Cao J, Wei Y, Lian J et al. Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling. Int. J. Mol. Med. 40(2), 378–388 (2017).
    • 32. Yang RH, Qi SH, Shu B et al. Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signalling pathway. Biosci. Rep. 36(4), e00364 (2016). •• Describes the relation between epidermal stem cells and Notch signaling pathway.
    • 33. Scherer SS, Pietramaggiori G, Matthews J et al. Poly-N-acetyl glucosamine nanofibers: a new bioactive material to enhance diabetic wound healing by cell migration and angiogenesis. Ann. Surg. 250(2), 322–330 (2009).
    • 34. Rousselle P, Montmasson M, Garnier C. Extracellular matrix contribution to skin wound re-epithelialization. Matrix Biol. 75-76, 12–26 (2019).
    • 35. Kim MH, Wu WH, Choi JH et al. Galectin-1 from conditioned medium of three-dimensional culture of adipose-derived stem cells accelerates migration and proliferation of human keratinocytes and fibroblasts. Wound Repair Regen. 26(Suppl. 1), S9–S18 (2018).
    • 36. Brennan MR, Milne CT, Agrell-Kann M et al. Clinical Evaluation of a Skin Protectant for the Management of Incontinence-Associated Dermatitis: An Open-Label, Nonrandomized, Prospective Study. J. Wound Ostomy Continence. Nurs. 44(2), 172–180 (2017).
    • 37. Xu Y, Zhu X, Hahm HS et al. Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules. Proc. Natl Acad. Sci. USA 107(18), 8129–8134 (2010).
    • 38. Li J, Fu X, Sheng Z et al. Ectopia of epidermal stem cells on wound edge during wound healing process. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 20(3), 264–267 (2006).
    • 39. Thomsen MS, Routhe LJ, Moos T. The vascular basement membrane in the healthy and pathological brain. J. Cereb. Blood Flow Metab. 37(10), 3300–3317 (2017).
    • 40. Wilkinson HN, Hardman MJ. Wound senescence: a functional link between diabetes and ageing? Exp. Dermatol. doi:10.1111/exd.14082 ( 2020).
    • 41. Franca RA, Esteves ABA, Borges CM et al. Advanced glycation end-products (AGEs) accumulation in skin: relations with chronic kidney disease-mineral and bone disorder. J. Bras. Nefrol. 39(3), 253–260 (2017).
    • 42. Hu SC, Lan CE. High-glucose environment disturbs the physiologic functions of keratinocytes: focusing on diabetic wound healing. J. Dermatol. Sci. 84(2), 121–127 (2016).
    • 43. Maltese G, Karalliedde J, Rapley H et al. A pilot study to evaluate the efficacy of class IV lasers on nonhealing neuroischemic diabetic foot ulcers in patients with type 2 diabetes. Diabetes Care 38(10), e152–153 (2015).
    • 44. Duckworth WC, Fawcett J, Reddy S et al. Insulin-degrading activity in wound fluid. J. Clin. Endocrinol. Metab. 89(2), 847–851 (2004).
    • 45. Wilkins JR, Pike DB, Gibson CC et al. Differential effects of cyclic stretch on bFGF- and VEGF-induced sprouting angiogenesis. Biotechnol. Prog. 30(4), 879–888 (2014).
    • 46. Olszewska-Pazdrak B, Hein TW, Olszewska P et al. Chronic hypoxia attenuates VEGF signaling and angiogenic responses by downregulation of KDR in human endothelial cells. Am. J. Physiol. Cell. Physiol. 296(5), C1162–1170 (2009).
    • 47. Schmidt MHH, Bicker F, Nikolic I et al. Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nat. Cell Biol. 11(7), 873–880 (2009).
    • 48. Shi Y, Shu B, Yang R et al. Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately. Stem Cell Res. Ther. 6(1), 120 (2015).