Skip to main content

Advertisement

SpringerLink
Log in

Different Trypanosoma cruzi calreticulin domains mediate migration and proliferation of fibroblasts in vitro and skin wound healing in vivo

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

Calreticulin is an endoplasmic reticulum-resident, calcium-binding, stress-produced, chaperone protein that serves multiple functions and is widely distributed in eukaryotic cells. Exogenously applied recombinant calreticulin solution, markedly enhanced the rate and quality of skin wound healing. These modulatory effects are more efficient than commercially available topic platelet-derived growth factor ointments (Regranex®). Trypanosoma cruzi calreticulin is more effective in equimolar terms to human counterpart in accelerating skin wound healing. While the effect of externally added recombinant parasite calreticulin on wound healing has been reported, the domains responsible for these modulatory effects have not yet been established. Here, recombinant parasite calreticulin and some of its domains were tested to assess their influence in increasing proliferation and migration of fibroblasts in vitro and rat skin wound healing in vivo. Herein, we propose that Trypanosoma cruzi whole calreticulin or some of its domains are differentially involved in the modulation of wound-healing cell migration and proliferation, and cosmetic outcome. Therefore, precise combination of the parasite protein and its domains could allow us to tailor-specific desired effects during the skin wound-healing process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Abello-Caceres P, Pizarro-Bauerle J, Rosas C, Maldonado I, Aguilar-Guzman L, Gonzalez C, Ramirez G, Ferreira J, Ferreira A (2016) Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection? BMC Cancer 16:731

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Arias JI, Sepulveda C, Bravo P, Hamilton-West C, Maldonado I, Ferreira A (2015) Comparative effect of human and Trypanosoma cruzi calreticulin in wound healing. J Tissue Eng Regen Med 9:41–54

    Article  CAS  Google Scholar 

  3. Baldo BA (2014) Side effects of cytokines approved for therapy. Drug Saf 37:921–943

    Article  PubMed  CAS  Google Scholar 

  4. Bayat A, McGrouther DA, Ferguson MWJ (2003) Skin scarring. Brit Med J 326:88–92

    Article  PubMed  CAS  Google Scholar 

  5. Brem H, Tomic-Canic M (2007) Cellular and molecular basis of wound healing in diabetes. J Clin Invest 117:1219–1222

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Briquez PS, Hubbell JA, Martino MM (2015) Extracellular matrix-inspired growth factor delivery systems for skin wound healing. Adv Wound Care 4:479–489

    Article  Google Scholar 

  7. Burns K, Duggan B, Atkinson EA, Famulski KS, Nemer M, Bleackley RC, Michalak M (1994) Modulation of gene expression by calreticulin binding to the glucocorticoid receptor. Nature 367:476–480

    Article  PubMed  CAS  Google Scholar 

  8. Cheng B, Liu H-W, Fu X-B, Sun T-Z, Sheng Z-Y (2007) Recombinant human platelet-derived growth factor enhanced dermal wound healing by a pathway involving ERK and c-fos in diabetic rats. J Dermatol Sci 45:193–201

    Article  PubMed  CAS  Google Scholar 

  9. DiPietro LA (2016) Angiogenesis and wound repair: when enough is enough. J Leukoc Biol 100:979–984

    Article  PubMed  CAS  Google Scholar 

  10. Falanga V (2005) Wound healing and its impairment in the diabetic foot. Lancet 366:1736–1743

    Article  PubMed  Google Scholar 

  11. Fernandes KJ, McKenzie IA, Mill P, Smith KM, Akhavan M, Barnabe-Heider F, Biernaskie J, Junek A, Kobayashi NR, Toma JG, Kaplan DR, Labosky PA, Rafuse V, Hui CC, Miller FD (2004) A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol 6:1082–1093

    Article  PubMed  CAS  Google Scholar 

  12. Ferreira V, Molina MaC, Valck C, Rojas Á, Aguilar L, Ramírez G, Schwaeble W, Ferreira A (2004) Role of calreticulin from parasites in its interaction with vertebrate hosts. Mol Immunol 40:1279–1291

    Article  PubMed  CAS  Google Scholar 

  13. Ferreira V, Valck C, Sanchez G, Gingras A, Tzima S, Molina MC, Sim R, Schwaeble W, Ferreira A (2004) The classical activation pathway of the human complement system is specifically inhibited by calreticulin from Trypanosoma cruzi. J Immunol 172:3042–3050

    Article  PubMed  CAS  Google Scholar 

  14. Frykberg RG, Banks J (2015) Challenges in the treatment of chronic wounds. Adv Wound Care 4:560–582

    Article  Google Scholar 

  15. Galiano RD, Michaels VJ, Dobryansky M, Levine JP, Gurtner GC (2004) Quantitative and reproducible murine model of excisional wound healing. Wound Repair Regen 12:485–492

    Article  PubMed  Google Scholar 

  16. Game FL, Apelqvist J, Attinger C, Hartemann A, Hinchliffe RJ, Löndahl M, Price PE, Jeffcoate WJ, On behalf of the International Working Group on the Diabetic Foot (IWGDF) (2016) Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review. Diabetes Metab Res Rev 32:154–168

    Article  PubMed  Google Scholar 

  17. Garrido O, Letelier R, Rosas C, Fuenzalida M, Ferreira A, Lemus D (2010) Betamethasone inhibits tumor development, microvessel density and prolongs survival in mice with a multiresistant adenocarcinoma TA3. Biol Res 43:317–322

    Article  PubMed  CAS  Google Scholar 

  18. Gold LI, Eggleton P, Sweetwyne MT, Van Duyn LB, Greives MR, Naylor SM, Michalak M, Murphy-Ullrich JE (2010) Calreticulin: non-endoplasmic reticulum functions in physiology and disease. FASEB 24:665–683

    Article  CAS  Google Scholar 

  19. Gold LI, Rahman M, Blechman KM, Greives MR, Churgin S, Michaels J, Callaghan MJ, Cardwell NL, Pollins AC, Michalak M, Siebert JW, Levine JP, Gurtner GC, Nanney LB, Galiano RD, Cadacio CL (2006) Overview of the role for calreticulin in the enhancement of wound healing through multiple biological effects. J Investig Dermatol Symp Proc 11:57–65

    Article  PubMed  CAS  Google Scholar 

  20. Gonzalez A, Valck C, Sanchez G, Hartel S, Mansilla J, Ramirez G, Fernandez MS, Arias JL, Galanti N, Ferreira A (2015) Trypanosoma cruzi calreticulin topographical variations in parasites infecting murine macrophages. Am J Trop Med Hyg 92:887–897

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Gowda S, Weinstein DA, Blalock TD, Gandhi K, Mast BA, Chin G, Schultz GS (2015) Topical application of recombinant platelet-derived growth factor increases the rate of healing and the level of proteins that regulate this response. Int Wound J 12:564–571

    Article  PubMed  Google Scholar 

  22. Greenhalgh DG, Sprugel KH, Murray MJ, Ross R (1990) PDGF and FGF stimulate wound healing in the genetically diabetic mouse. Am J Pathol 136:1235–1246

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Greives MR, Samra F, Pavlides SC, Blechman KM, Naylor S-M, Woodrell CD, Cadacio C, Levine JP, Bancroft TA, Michalak M, Warren SM, Gold LI (2012) Exogenous calreticulin improves diabetic wound healing. Wound Repair Regen 20:715–730

    Article  PubMed  Google Scholar 

  24. Hinz B (2007) Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 127:526–537

    Article  PubMed  CAS  Google Scholar 

  25. Hosgood G (2006) Stages of wound healing and their clinical relevance. Vet Clin North Am Small Anim Pract 36:667–685

    Article  PubMed  Google Scholar 

  26. Iruela-Arispe ML, Dvorak HF (1997) Angiogenesis: a dynamic balance of stimulators and inhibitors. Thromb Haemost 78:672–677

    Article  PubMed  CAS  Google Scholar 

  27. Johnson V, Webb T, Norman A, Coy J, Kurihara J, Regan D, Dow S (2017) Activated mesenchymal stem cells interact with antibiotics and host innate immune responses to control chronic bacterial infections. Sci Rep 7:9575

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jozic I, Vukelic S, Stojadinovic O, Liang L, Ramirez HA, Pastar I, Tomic Canic M (2017) Stress signals, mediated by membranous glucocorticoid receptor, activate PLC/PKC/GSK-3beta/beta-catenin pathway to inhibit wound closure. J Invest Dermatol 137:1144–1154

    Article  PubMed  CAS  Google Scholar 

  29. Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233

    Article  PubMed  CAS  Google Scholar 

  30. Labriola C, Cazzulo JJ, Parodi AJ (1999) Trypanosoma cruzi calreticulin is a lectin that binds monoglucosylated oligosaccharides but not protein moieties of glycoproteins. Mol Biol Cell 10:1381–1394

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Langer A, Rogowski W (2009) Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers. BMC Health Serv Res 9:115

    Article  PubMed  PubMed Central  Google Scholar 

  32. Le Provost GS, Pullar CE (2015) [beta]2-adrenoceptor activation modulates skin wound healing processes to reduce scarring. J Invest Dermatol 135:279–288

    Article  PubMed  CAS  Google Scholar 

  33. Lopez NC, Valck C, Ramirez G, Rodriguez M, Ribeiro C, Orellana J, Maldonado I, Albini A, Anacona D, Lemus D, Aguilar L, Schwaeble W, Ferreira A (2010) Antiangiogenic and antitumor effects of Trypanosoma cruzi Calreticulin. PLoS Negl Trop Dis 4:e730

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. McLaughlin PJ, Cain JD, Titunick MB, Sassani JW, Zagon IS (2017) Topical naltrexone is a safe and effective alternative to standard treatment of diabetic wounds. Adv Wound Care 6:279–288

    Article  Google Scholar 

  35. Michalak M, Corbett EF, Mesaeli N, Nakamura K, Opas M (1999) Calreticulin: one protein, one gene, many functions. Biochem J 344:281–292

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Nanney LB, Woodrell CD, Greives MR, Cardwell NL, Pollins AC, Bancroft TA, Chesser A, Michalak M, Rahman M, Siebert JW, Gold LI (2008) Calreticulin enhances porcine wound repair by diverse biological effects. Am J Pathol 173:610–630

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Okwueze MI, Cardwell NL, Pollins AC, Nanney LB (2007) Modulation of porcine wound repair with a transfected ErbB3 gene and relevant EGF-like ligands. J Invest Dermatol 127:1030–1041

    Article  PubMed  CAS  Google Scholar 

  38. Park SA, Raghunathan VK, Shah NM, Teixeira L, Motta MJ, Covert J, Dubielzig R, Schurr M, Isseroff RR, Abbott NL, McAnulty J, Murphy CJ (2014) PDGF-BB does not accelerate healing in diabetic mice with splinted skin wounds. PLoS One 9:e104447

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Persson U, Willis M, Odegaard K, Apelqvist J (2002) The cost-effectiveness of treating diabetic lower extremity ulcers with becaplermin (Regranex): a core model with an application using Swedish cost data. Value Health 3(Suppl 1):39–46

    Google Scholar 

  40. Pike SE, Yao L, Setsuda J, Jones KD, Cherney B, Appella E, Sakaguchi K, Nakhasi H, Atreya CD, Teruya-Feldstein J, Wirth P, Gupta G, Tosato G (1999) Calreticulin and calreticulin fragments are endothelial cell inhibitors that suppress tumor growth. Blood 94:2461–2468

    PubMed  CAS  Google Scholar 

  41. Piperigkou Z, Gotte M, Theocharis AD, Karamanos NK (2017) Insights into the key roles of epigenetics in matrix macromolecules-associated wound healing. Adv Drug Deliv Rev. https://doi.org/10.1016/j.addr.2017.10.008

    Article  PubMed  Google Scholar 

  42. Rajkumar VS, Shiwen X, Bostrom M, Leoni P, Muddle J, Ivarsson M, Gerdin B, Denton CP, Bou-Gharios G, Black CM, Abraham DJ (2006) Platelet-derived growth factor-beta receptor activation is essential for fibroblast and pericyte recruitment during cutaneous wound healing. Am J Pathol 169:2254–2265

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Rämet M, Lanot R, Zachary D, Manfruelli P (2002) JNK signaling pathway is required for efficient wound healing in drosophila. ‎Dev Biol 241:145–156

    PubMed  Google Scholar 

  44. Ramirez G, Valck C, Molina MC, Ribeiro CH, Lopez N, Sanchez G, Ferreira VP, Billetta R, Aguilar L, Maldonado I, Cattan P, Schwaeble W, Ferreira A (2011) Trypanosoma cruzi calreticulin: a novel virulence factor that binds complement C1 on the parasite surface and promotes infectivity. Immunobiology 216:265–273

    Article  PubMed  CAS  Google Scholar 

  45. Shaw TJ, Martin P (2009) Wound repair at a glance. ‎J Cell Sci 122:3209–3213

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Sim RB, Moestrup SK, Stuart GR, Lynch NJ, Lu J, Schwaeble WJ, Malhotra R (1998) Interaction of C1q and the collectins with the potential receptors calreticulin (cClqR/collectin receptor) and megalin. Immunobiology 199:208–224

    Article  PubMed  CAS  Google Scholar 

  47. Stojadinovic O, Brem H, Vouthounis C, Lee B, Fallon J, Stallcup M, Merchant A, Galiano RD, Tomic-Canic M (2005) Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol 167:59–69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Toma JG, Akhavan M, Fernandes KJ, Barnabe-Heider F, Sadikot A, Kaplan DR, Miller FD (2001) Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 3:778–784

    Article  PubMed  CAS  Google Scholar 

  49. Valck C, Ramirez G, Lopez N, Ribeiro CH, Maldonado I, Sanchez G, Ferreira VP, Schwaeble W, Ferreira A (2010) Molecular mechanisms involved in the inactivation of the first component of human complement by Trypanosoma cruzi calreticulin. Mol Immunol 47:1516–1521

    Article  PubMed  CAS  Google Scholar 

  50. Zhang Y, Liu L, Jin L, Yi X, Dang E, Yang Y, Li C, Gao T (2014) Oxidative stress-induced calreticulin expression and translocation: new insights into the destruction of melanocytes. J Invest Dermatol 134:183–191

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Research in the author’s laboratory was supported by the FONDECYT 11130257 Grant of CONICYT Chile. We thank Dr. David Carrino for his helpful suggestions in the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of Clinical Science, Faculty of Veterinary and Animal Science, University of Chile, Santiago, Chile

    Jose Ignacio Arias, Natalia Parra, Carolina Beato & Cristian Gabriel Torres

  2. Department of Preventive Medicine, Faculty of Veterinary and Animal Science, University of Chile, Santiago, Chile

    Christopher Hamilton-West

  3. Department of Morphological Sciences, Faculty of Science, Universidad San Sebastian, Santiago, Chile

    Carlos Rosas

  4. Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile

    Arturo Ferreira

Authors
  1. Jose Ignacio Arias
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalia Parra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carolina Beato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cristian Gabriel Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher Hamilton-West
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlos Rosas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Arturo Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jose Ignacio Arias.

Ethics declarations

Research involving human and animal rights

All animal procedures were approved by the local Animal Bioethics Committee in accordance with the International Guiding Principles for Biomedical Research Involving Animals, were developed by the Council for International Organizations of Medical Sciences (CIOMS), and were supervised by trained veterinary medical staff.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arias, J.I., Parra, N., Beato, C. et al. Different Trypanosoma cruzi calreticulin domains mediate migration and proliferation of fibroblasts in vitro and skin wound healing in vivo. Arch Dermatol Res 310, 639–650 (2018). https://doi.org/10.1007/s00403-018-1851-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-018-1851-7

Keywords

Search

Navigation