Advertisement

Journal of Molecular Histology

, Volume 49, Issue 3, pp 277–287 | Cite as

Effects of CD100 promote wound healing in diabetic mice

  • Fang Wang
  • Bei Liu
  • Zhou Yu
  • Tong Wang
  • Yajuan Song
  • Ran Zhuang
  • Yonghong Wu
  • Yingjun Su
  • Shuzhong Guo
Original Paper
  • 131 Downloads

Abstract

Diabetes is a condition that causes delayed wound healing and results in chronic wounds. CD100 has been reported to promote and induce potent and obvious angiogenesis both in vivo and in vitro studies, the absence of which are a main cause of the diabetic chronic wound. In the present study, we investigated the effects of application of soluble CD100 on wound healing in diabetic mice. Four 5-mm full-thickness dermal wounds were made on each male db/db mouse. 12 mice from CD100 group were subcutaneously injected with 250 ng of CD100 (50 µl) per wound, in addition, 12 mice were injected with the same volume phosphate-balanced solution as the control. The animals were treated every other day until the wounds healed completely. Images were obtained to calculate the area ratio of the original area. HE and Masson’s trichrome staining were used for histological examination. Collagen remodeling, angiogenesis and wound bed inflammation were evaluated by immunohistochemical staining and western blot. We demonstrated that CD100 had distinct functions during the wound healing process. Histological and western blotting analysis showed a more organized epithelium and dermis, more collagen fibers, higher angiogenesis and lower inflammation in the CD100 group than in the PBS group. These findings suggest that CD100 may accelerate wound healing in diabetic mice by promoting angiogenesis in the wound and by reducing the inflammatory response.

Keywords

Wound healing CD100 Diabetes Angiogenesis Inflammation 

Abbreviations

bFGF

Basic fibroblast growth factor

CD100

Cluster of differentiation 100

CD31

Cluster of differentiation 31

CD34

Cluster of differentiation 34

CD68

Cluster of differentiation 68

CD72

Cluster of differentiation 72

Col I

Collagen type I

Col III

Collagen type III

DAB

Diaminobenzidine

HGF

Human growth factor

IL-6

Interleukin-6

PBS

Phosphate-balanced solution

TNF-α

Tumor necrosis factor alpha

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81401598). The authors would like to thank Prof. Yi Chenggang for helpful discussions of the data and Dr. Chenlin and Liang Yingzi for assistance with the morphological evaluation.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest to disclose.

Supplementary material

10735_2018_9767_MOESM1_ESM.jpg (12 kb)
Supplementary Figure 1 Body weights of db/db mice and db/m mice. (JPG 12 KB)
10735_2018_9767_MOESM2_ESM.jpg (14 kb)
Supplementary Figure 2 Blood glucoseof db/db mice and db/m mice. (JPG 13 KB)
10735_2018_9767_MOESM3_ESM.jpg (355 kb)
Supplementary Figure 3 VEGF staining analysis. IHC results showing the VEGF-stained wound tissues from days 7, 13 and 21 in the PBS- and CD100-treated groups. Magnification 400×. Bars=100 μm. (JPG 355 KB)

References

  1. Ahmed S, ShahSaeid AN (2017) The role of phytochemicals in the inflammatory phase of wound healing. Int J Mol Sci 18(5):1068CrossRefGoogle Scholar
  2. Algenstaedt P, Schaefer C, Biermann T, Hamann A, Schwarzloh B, Greten H, Ruther W et al (2003) Microvascular alterations in diabetic mice correlate with level of hyperglycemia. Diabetes 52(2):542–549CrossRefPubMedGoogle Scholar
  3. Altavilla D, Saitta A, Cucinotta D, Galeano M, Deodato B, Colonna M, Squadrito F et al (2001) Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in the genetically diabetic mouse. Diabetes 50(3):667–674CrossRefPubMedGoogle Scholar
  4. An YL, Wei W, Jing H, Ming LG, Liu SY, Jin Y (2015) Bone marrow mesenchymal stem cell aggregate: an optimal cell therapy for full-layer cutaneous wound vascularization and regeneration. Sci Rep 5:17036CrossRefPubMedPubMedCentralGoogle Scholar
  5. Apelqvist J (2012) Diagnostics and treatment of the diabetic foot. Endocrine 41(3):384–397CrossRefPubMedGoogle Scholar
  6. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16(5):585–601CrossRefPubMedGoogle Scholar
  7. Basile JR, Barac A, Zhu TQ, Guan KL, Gutkind JS (2004) Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 64(15):5212–5224CrossRefPubMedGoogle Scholar
  8. Basile JR, Afkhami T, Gutkind JS (2005) Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Mol Cell Biol 25(16):6889–6898CrossRefPubMedPubMedCentralGoogle Scholar
  9. Basile JR, Castilho RM, Williams VP, Gutkind JS (2006) Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci USA 103(24):9017–9022CrossRefPubMedPubMedCentralGoogle Scholar
  10. Binmadi NO, Proia P, Zhou H, Yang YH, Basile JR (2011) Rho-mediated activation of PI(4)P5K and lipid second messengers is necessary for promotion of angiogenesis by Semaphorin 4D. Angiogenesis 14(3):309–319CrossRefPubMedGoogle Scholar
  11. Bruhn OB, Korzon BA, Gabig CM, Olszewski P, Węgrzyn A, Jakóbkiewicz BJ (2012) Molecular factors involved in the development of diabetic foot syndrome. Acta Biochim Pol 59(4):507–513Google Scholar
  12. Chabbert-de PI, Marie-Cardine A, Pasterkamp RJ, Schiavon V, Tamagnone L, Thomasset N, Boumsell L et al (2005) Soluble CD100 functions on human monocytes and immature dendritic cells require plexin C1 and plexin B1, respectively. Int Immunol 17:439–447CrossRefGoogle Scholar
  13. Conrotto P, Valdembri D, Corso S, Sweini G, Tamagone L, Comoglio PM, Giordano S et al (2005) Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 105(11):4321–4329CrossRefPubMedGoogle Scholar
  14. Deborah AW, Megumi W, Olivia G, Stephanie E, Rieder GS, Shane JF, Wendy LH et al (2012) The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal γδ T cell function. Immunity 37(2):314–325CrossRefGoogle Scholar
  15. Diegelmann RF, Evans MC (2004) Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci 9:283–289CrossRefPubMedGoogle Scholar
  16. Doupis J, Rahangdale S, Gnardellis C, Pena SE, Malhotra A, Veves A (2011) Effects of diabetes and obesity on vascular reactivity, inflammatory cytokines, and growth factors. Obesity (Silver Spring) 19(4):729–735CrossRefGoogle Scholar
  17. Falanga V (2005) Wound healing and its impairment in the diabetic foot. Lancet 366(9498):1736–1743CrossRefPubMedGoogle Scholar
  18. Fazzari P, Penachioni J, Gianola S, Rossi F, Eickholt B, Maina F, Tamagnone L et al (2007) Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis. BMC Dev Biol 7:55CrossRefPubMedPubMedCentralGoogle Scholar
  19. Galiano RD, Michaels J, Dobryansky M, Levine JP, Gurtner GC (2004) Quantitative and reproducible murine model of excisional wound healing. Wound Repair Regen 12:485–492CrossRefPubMedGoogle Scholar
  20. Giacobini P, Messina A, Morello F, Ferraris N, Corso S, Penachioni J et al (2008) Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex. J Cell Biol 183:555–566CrossRefPubMedPubMedCentralGoogle Scholar
  21. Giraudon P, Vincent P, Vuaillat C (2004) Semaphorin CD100 from activated T lymphocytes induces process extension collapse in oligodendrocytes and death of immature neural cells. J Immunol 172(2):1246–1255CrossRefPubMedGoogle Scholar
  22. Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453(7193):314–321CrossRefPubMedGoogle Scholar
  23. Hiroyuki K, Yukiomi N, Taeko Y et al (2017) Influence of nicotine on choline-deficient, L-amino acid-defined diet-induced non-alcoholic steatohepatitis in rats. PLoS ONE 12(6):e0180475CrossRefGoogle Scholar
  24. Ishida I, Kumanogoh A, Suzuki K, Akahani S, Noda K, Kikutani H (2003) Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses. Int Immunol 15:1027–1034CrossRefPubMedGoogle Scholar
  25. Ishrath A, Vivekananda GS, Jacob G, Verena P, Claus PS, Sergiu-Bogdan C, Kerstin B, Elisabete AF (2012) Carnosine enhances diabetic wound healing in the db/db mouse model of type 2 diabetes. Amino Acids 43:127–134CrossRefGoogle Scholar
  26. Ito Y, Oinuma I, Katoh H, Kaibuchi K, Negishi M (2006) Sema4D/plexin-B1 activates GSK-3β through R-Ras GAP activity inducing growth cone collapse. EMBO Rep 7(7):704–709CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kumanogoh A, Kikutani H (2004) Biological functions and signaling of a transmembrane semaphorin, CD100/Sema4D. Cell Mol Life Sci 61(3):292–300CrossRefPubMedGoogle Scholar
  28. Kumanogoh A, Suzuki K, Ch’ng ES, Watanabe C, Marukawa S, Takegahara N, Kikutani H et al (2002) Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. J Immunol 169(3):1175–1181CrossRefPubMedGoogle Scholar
  29. Lai AZ, Abella JV, Park M (2009) Crosstalk in Met receptor oncogenesis. Trends Cell Biol 19(10):542–551CrossRefPubMedGoogle Scholar
  30. Li XY, Chen SZ, Li WZ, Li YJ, Lv XX, Li J, Li JQ et al (2008) Differentiation of the pericyte in wound healing: The precursor, the process, and the role of the vascular endothelial cell view issue TOC. Wound Repair Regen 16(3):346–355CrossRefGoogle Scholar
  31. Liu H, Duan ZL, Tang J, Lv QM, Rong MQ, Lai R (2014) A short peptide from frog skin accelerates diabetic wound healing. FEBS J 281(20):4633–4643CrossRefPubMedGoogle Scholar
  32. Martin A, Komada MR, Sane DC (2003) Abnormal angiogenesis in diabetes mellitus. Med Res Rev 23(2):117–145CrossRefPubMedGoogle Scholar
  33. Niwano Y, Koga H, Sakai A, Kanai K, Hamaguchi H, Uchida M, Tachikawa T (1996) Wound healing effect of malotilate in rats. Arzneimittel-forschung 46(4):450–455PubMedGoogle Scholar
  34. Rian QL, Ryan MS, James M et al (2015) Hagberg. Chronic endurance exercise affects paracrine action of CD31+ and CD34+ cells on endothelial tube formation. Am J Physiol Heart Circ Physiol 309(3):H409-H420Google Scholar
  35. Shu C, Smith SM, Melrose J (2016) The heparan sulphate deficient Hspg2 exon 3 null mouse displays reduced deposition of TGF-β1 in skin compared to C57BL/6 wild type mice. J Mol Histol 47(3):365–374CrossRefPubMedGoogle Scholar
  36. Smith EP, Shanks K, Lipsky MM, DeTolla LJ, Keegan AD, Chapoval SP (2011) Expression of neuroimmune semaphorins 4A and 4D and their receptors in the lung is enhanced by allergen and vascular endothelial growth factor. BMC Immunol 12:30CrossRefPubMedPubMedCentralGoogle Scholar
  37. Snyder RJ (2005) Treatment of nonhealing ulcers with allografts. Clin Dermatol 23(4):388–395CrossRefPubMedGoogle Scholar
  38. Tsubame NYS, Kanazawa S, Makiko K, Kayoko O, Lin L, Ayato H, Rica T et al (2017) Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice. PLoS ONE 12(5):e0178232CrossRefGoogle Scholar
  39. Yang L, Zheng Z, Zhou Q, Bai X, Fan L, Yang C, Su L, Hu D (2017) miR-155 promotes cutaneous wound healing through enhanced keratinocytes migration by MMP-2. J Mol Histol 48(2):147–155CrossRefPubMedGoogle Scholar
  40. Zhao RL, Liang H, Clarke E, Jackson C, Xue ML (2016) Inflammation in chronic wounds. Int J Mol Sci 17(2085):1–14Google Scholar
  41. Zhao B, Zhang Y, Han S, Zhang W, Zhou Q, Guan H, Liu J, Shi J, Su L, Hu D (2017) Exosomes derived from human amniotic epithelial cells accelerate wound healing and inhibit scar formation. J Mol Histol 48(2):121–132CrossRefPubMedGoogle Scholar
  42. Zhu L, Bergmeier W, Wu J, Jiang H, Stalker TJ, Cieslak M, Kikutani H et al (2007) Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc Natl Acad Sci 104(5):1621–1626CrossRefPubMedPubMedCentralGoogle Scholar
  43. Zhu L, Stalker TJ, Fong KP, Jiang H, Tran A, Crichton I, Kikutani H et al (2009) Disruption of SEMA4D ameliorates interaction that accelerates atherosclerosis. Cardiovasc Res 105(3):361–371Google Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Fang Wang
    • 1
    • 2
  • Bei Liu
    • 1
    • 3
  • Zhou Yu
    • 1
  • Tong Wang
    • 1
  • Yajuan Song
    • 1
  • Ran Zhuang
    • 4
  • Yonghong Wu
    • 3
  • Yingjun Su
    • 1
  • Shuzhong Guo
    • 1
  1. 1.Department of Plastic and Reconstructive Surgery, Xijing HospitalThe Fourth Military Medical UniversityXi’anChina
  2. 2.Department of Medical CosmetologyThe First Affiliated Hospital of Xian Medical UniversityXi’anChina
  3. 3.Department of Medical TechnologyXian Medical UniversityXi’anChina
  4. 4.Department of Transplantation Immunology Laboratory of Basic Medical CollegeThe Fourth Military Medical UniversityXi’anChina

Personalised recommendations