The role of mast cells in cutaneous wound healing in streptozotocin-induced diabetic mice
- 595 Downloads
- 11 Citations
Abstract
Mast cells (MCs) reside in cutaneous tissue, and an increment of MCs is suggested to induce vascular regression in the process of wound healing. To clarify participation of MCs in diabetic cutaneous wound healing, we created an excisional wound on diabetic mice 4 weeks after streptozotocin injections and subsequently investigated the healing processes for 49 days, comparing them with control mice. The rate of wound closure was not markedly different between the diabetic and control mice. In the proliferative phase at days 7 and 14, neovascularization in the wound was weaker in diabetic mice than in control mice. In the remodeling phase at day 21 and afterward, rapid vascular regression occurred in control mice; however, neovascularization was still observed in diabetic mice where the number of vessels in granulation tissues was relatively higher than in control mice. In the remodeling phase of the control mice, MCs within the wound began to increase rapidly and resulted in considerable accumulation, whereas the increment of MCs was delayed in diabetic mice. In addition, the number of fibroblast growth factor (FGF)- or vascular endothelial growth factor (VEGF)-immunopositive hypertrophic fibroblast-like spindle cells and c-Kit-positive/VEGFR2-positive/FcεRIα-negative endothelial progenitor cells (EPCs) were higher in diabetic wounds. In conclusion, neovascularization in the proliferative phase and vascular regression in the remodeling phase were impaired in diabetic mice. The delayed increment of MCs and sustained angiogenic stimuli by fibroblast-like spindle cells and EPCs may inhibit vascular regression in the remodeling phase and impair the wound-healing process in diabetic mice.
Keywords
Wound healing Mast cells Endothelial progenitor cells Angiogenesis Vascular regressionReferences
- 1.Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341:738–746PubMedCrossRefGoogle Scholar
- 2.Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453:314–321PubMedCrossRefGoogle Scholar
- 3.Iruela-Arispe ML, Dvorak HF (1997) Angiogenesis: a dynamic balance of stimulators and inhibitors. Thromb Haemost 78:672–677PubMedGoogle Scholar
- 4.Peplow PV, Baxter GD (2012) Gene expression and release of growth factors during delayed wound healing: a review of studies in diabetic animals and possible combined laser phototherapy and growth factor treatment to enhance healing. Photomed Laser Surg 30:617–636PubMedCrossRefGoogle Scholar
- 5.Tahergorabi Z, Khazaei M (2012) Imbalance of angiogenesis in diabetic complications: the mechanisms. Int J Prev Med 3:827–838PubMedCrossRefPubMedCentralGoogle Scholar
- 6.Martin A, Komada MR, Sane DC (2003) Abnormal angiogenesis in diabetes mellitus. Med Res Rev 23:117–145PubMedCrossRefGoogle Scholar
- 7.Keswani SG, Katz AB, Lim FY, Zoltick P, Radu A, Alaee D, Herlyn M, Crombleholme TM (2004) Adenoviral mediated gene transfer of PDGF-B enhances wound healing in type I and type II diabetic wounds. Wound Repair Regen 12:497–504PubMedCrossRefGoogle Scholar
- 8.Kwon DS, Gao X, Liu YB, Dulchavsky DS, Danyluk AL, Bansal M, Chopp M, McIntosh K, Arbab AS, Dulchavsky SA, Gautam SC (2008) Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats. Int Wound J 5:453–463PubMedCrossRefGoogle Scholar
- 9.Maharlooei MK, Bagheri M, Solhjou Z, Jahromi BM, Akrami M, Rohani L, Monabati A, Noorafshan A, Omrani GR (2011) Adipose tissue derived mesenchymal stem cell (AD-MSC) promotes skin wound healing in diabetic rats. Diabetes Res Clin Pract 93:228–234PubMedCrossRefGoogle Scholar
- 10.Starkey JR, Crowle PK, Taubenberger S (1988) Mast-cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis. Int J Cancer 42:48–52PubMedCrossRefGoogle Scholar
- 11.Noli C, Miolo A (2001) The mast cell in wound healing. Vet Dermatol 12:303–313PubMedCrossRefGoogle Scholar
- 12.Trautmann A, Toksoy A, Engelhardt E, Brocker EB, Gillitzer R (2000) Mast cell involvement in normal human skin wound healing: expression of monocyte chemoattractant protein-1 is correlated with recruitment of mast cells which synthesize interleukin-4 in vivo. J Pathol 190:100–106PubMedCrossRefGoogle Scholar
- 13.Egozi EI, Ferreira AM, Burns AL, Gamelli RL, Dipietro LA (2003) Mast cells modulate the inflammatory but not the proliferative response in healing wounds. Wound Repair Regen 11:46–54PubMedCrossRefGoogle Scholar
- 14.Antsiferova M, Martin C, Huber M, Feyerabend TB, Forster A, Hartmann K, Rodewald HR, Hohl D, Werner S (2013) Mast cells are dispensable for normal and activin-promoted wound healing and skin carcinogenesis. J Immunol 191:6147–6155PubMedCrossRefGoogle Scholar
- 15.Nauta AC, Grova M, Montoro DT, Zimmermann A, Tsai M, Gurtner GC, Galli SJ, Longaker MT (2013) Evidence that mast cells are not required for healing of splinted cutaneous excisional wounds in mice. PLoS One 8:e59167PubMedCrossRefPubMedCentralGoogle Scholar
- 16.Willenborg S, Eckes B, Brinckmann J, Krieg T, Waisman A, Hartmann K, Roers A, Eming SA (2014) Genetic ablation of mast cells redefines the role of mast cells in skin wound healing and bleomycin-induced fibrosis. J Invest Dermatol. doi: 10.1038/jid.2014.12 PubMedGoogle Scholar
- 17.Nishikori Y, Kakizoe E, Kobayashi Y, Shimoura K, Okunishi H, Dekio S (1998) Skin mast cell promotion of matrix remodeling in burn wound healing in mice: relevance of chymase. Arch Dermatol Res 290:553–560PubMedCrossRefGoogle Scholar
- 18.Shiota N, Nishikori Y, Kakizoe E, Shimoura K, Niibayashi T, Shimbori C, Tanaka T, Okunishi H (2010) Pathophysiological role of skin mast cells in wound healing after scald injury: study with mast cell-deficient W/W(V) mice. Int Arch Allergy Immunol 151:80–88PubMedCrossRefGoogle Scholar
- 19.Kim KL, Meng Y, Kim JY, Baek EJ, Suh W (2011) Direct and differential effects of stem cell factor on the neovascularization activity of endothelial progenitor cells. Cardiovasc Res 92:132–140PubMedCrossRefGoogle Scholar
- 20.Dentelli P, Rosso A, Balsamo A, Colmenares Benedetto S, Zeoli A, Pegoraro M, Camussi G, Pegoraro L, Brizzi MF (2007) C-KIT, by interacting with the membrane-bound ligand, recruits endothelial progenitor cells to inflamed endothelium. Blood 109:4264–4271PubMedCrossRefGoogle Scholar
- 21.Lan CC, Wu CS, Kuo HY, Huang SM, Chen GS (2009) Hyperglycaemic conditions hamper keratinocyte locomotion via sequential inhibition of distinct pathways: new insights on poor wound closure in patients with diabetes. Br J Dermatol 160:1206–1214PubMedCrossRefGoogle Scholar
- 22.Michaels J, Churgin SS, Blechman KM, Greives MR, Aarabi S, Galiano RD, Gurtner GC (2007) Db/db mice exhibit severe wound-healing impairments compared with other murine diabetic strains in a silicone-splinted excisional wound model. Wound Repair Regen 15:665–670PubMedCrossRefGoogle Scholar
- 23.Trousdale RK, Jacobs S, Simhaee DA, Wu JK, Lustbader JW (2009) Wound closure and metabolic parameter variability in a db/db mouse model for diabetic ulcers. J Surg Res 151:100–107PubMedCrossRefGoogle Scholar
- 24.Greenhalgh DG (2003) Tissue repair in models of diabetes mellitus: a review. Methods Mol Med 78:181–189PubMedGoogle Scholar
- 25.Mirza R, Koh TJ (2011) Dysregulation of monocyte/macrophage phenotype in wounds of diabetic mice. Cytokine 56:256–264PubMedCrossRefGoogle Scholar
- 26.Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ (2004) Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 53:195–199PubMedCrossRefGoogle Scholar
- 27.Fiorina P, Pietramaggiori G, Scherer SS, Jurewicz M, Mathews JC, Vergani A, Thomas G, Orsenigo E, Staudacher C, La Rosa S, Capella C, Carothers A, Zerwes HG, Luzi L, Abdi R, Orgill DP (2010) The mobilization and effect of endogenous bone marrow progenitor cells in diabetic wound healing. Cell Transplant 19:1369–1381PubMedCrossRefGoogle Scholar
- 28.Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, Krasich R, Temm CJ, Prchal JT, Ingram DA (2007) Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 109:1801–1809PubMedCrossRefPubMedCentralGoogle Scholar
- 29.Herdrich BJ, Lind RC, Liechty KW (2008) Multipotent adult progenitor cells: their role in wound healing and the treatment of dermal wounds. Cytotherapy 10:543–550PubMedCrossRefGoogle Scholar
- 30.Liu SH, Sheu WH, Lee MR, Lee WJ, Yi YC, Yang TJ, Jen JF, Pan HC, Shen CC, Chen WB, Tien HR, Sheu ML (2013) Advanced glycation end product Nepsilon-carboxymethyllysine induces endothelial cell injury: the involvement of SHP-1-regulated VEGFR-2 dephosphorylation. J Pathol 230:215–227PubMedCrossRefGoogle Scholar
- 31.Portero-Otin M, Pamplona R, Bellmunt MJ, Ruiz MC, Prat J, Salvayre R, Negre-Salvayre A (2002) Advanced glycation end product precursors impair epidermal growth factor receptor signaling. Diabetes 51:1535–1542PubMedCrossRefGoogle Scholar
- 32.Hur J, Yoon CH, Kim HS, Choi JH, Kang HJ, Hwang KK, Oh BH, Lee MM, Park YB (2004) Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol 24:288–293PubMedCrossRefGoogle Scholar
- 33.Lois N, McCarter RV, O’Neill C, Medina RJ, Stitt AW (2014) Endothelial progenitor cells in diabetic retinopathy. Front Endocrinol (Lausanne) 5:44Google Scholar
- 34.Ilan N, Mahooti S, Madri JA (1998) Distinct signal transduction pathways are utilized during the tube formation and survival phases of in vitro angiogenesis. J Cell Sci 111(Pt 24):3621–3631PubMedGoogle Scholar
- 35.Pepper MS, Vassalli JD, Orci L, Montesano R (1993) Biphasic effect of transforming growth factor-beta 1 on in vitro angiogenesis. Exp Cell Res 204:356–363PubMedCrossRefGoogle Scholar
- 36.Lindstedt KA, Wang Y, Shiota N, Saarinen J, Hyytiainen M, Kokkonen JO, Keski-Oja J, Kovanen PT (2001) Activation of paracrine TGF-beta1 signaling upon stimulation and degranulation of rat serosal mast cells: a novel function for chymase. FASEB J 15:1377–1388PubMedCrossRefGoogle Scholar
- 37.Galli SJ, Tsai M (2008) Mast cells: versatile regulators of inflammation, tissue remodeling, host defense and homeostasis. J Dermatol Sci 49:7–19PubMedCrossRefPubMedCentralGoogle Scholar
- 38.Iba Y, Shibata A, Kato M, Masukawa T (2004) Possible involvement of mast cells in collagen remodeling in the late phase of cutaneous wound healing in mice. Int Immunopharmacol 4:1873–1880PubMedCrossRefGoogle Scholar
- 39.Bevan D, Gherardi E, Fan TP, Edwards D, Warn R (2004) Diverse and potent activities of HGF/SF in skin wound repair. J Pathol 203:831–838PubMedCrossRefGoogle Scholar
- 40.Kitamura Y, Go S, Hatanaka K (1978) Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 52:447–452PubMedGoogle Scholar
- 41.Okayama Y, Kawakami T (2006) Development, migration, and survival of mast cells. Immunol Res 34:97–115PubMedCrossRefPubMedCentralGoogle Scholar
- 42.Ashman LK (1999) The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol 31:1037–1051PubMedCrossRefGoogle Scholar
- 43.Galli SJ, Tsai M, Wershil BK (1993) The c-kit receptor, stem cell factor, and mast cells. What each is teaching us about the others. Am J Pathol 142:965–974PubMedPubMedCentralGoogle Scholar
- 44.Tsai M, Takeishi T, Thompson H, Langley KE, Zsebo KM, Metcalfe DD, Geissler EN, Galli SJ (1991) Induction of mast cell proliferation, maturation, and heparin synthesis by the rat c-kit ligand, stem cell factor. Proc Natl Acad Sci USA 88:6382–6386PubMedCrossRefPubMedCentralGoogle Scholar
- 45.Dudeck A, Leist M, Rubant S, Zimmermann A, Dudeck J, Boehncke WH, Maurer M (2010) Immature mast cells exhibit rolling and adhesion to endothelial cells and subsequent diapedesis triggered by E- and P-selectin, VCAM-1 and PECAM-1. Exp Dermatol 19:424-434PubMedCrossRefGoogle Scholar
- 46.Zins SR, Amare MF, Tadaki DK, Elster EA, Davis TA (2010) Comparative analysis of angiogenic gene expression in normal and impaired wound healing in diabetic mice: effects of extracorporeal shock wave therapy. Angiogenesis 13:293–304PubMedCrossRefGoogle Scholar
- 47.Karimi K, Redegeld FA, Heijdra B, Nijkamp FP (1999) Stem cell factor and interleukin-4 induce murine bone marrow cells to develop into mast cells with connective tissue type characteristics in vitro. Exp Hematol 27:654–662PubMedCrossRefGoogle Scholar
- 48.Cavalher-Machado SC, de Lima WT, Damazo AS, de Frias Carvalho V, Martins MA, e Silva PM, Sannomiya P (2004) Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 24:552–558PubMedCrossRefGoogle Scholar
- 49.Wu L, Derynck R (2009) Essential role of TGF-beta signaling in glucose-induced cell hypertrophy. Dev Cell 17:35–48PubMedCrossRefPubMedCentralGoogle Scholar
- 50.Lee MJ, Kim J, Lee KI, Shin JM, Chae JI, Chung HM (2011) Enhancement of wound healing by secretory factors of endothelial precursor cells derived from human embryonic stem cells. Cytotherapy 13:165–178PubMedCrossRefGoogle Scholar
- 51.Broadley KN, Aquino AM, Hicks B, Ditesheim JA, McGee GS, Demetriou AA, Woodward SC, Davidson JM (1989) The diabetic rat as an impaired wound healing model: stimulatory effects of transforming growth factor-beta and basic fibroblast growth factor. Biotechnol Ther 1:55–68PubMedGoogle Scholar