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Influence of Mesenchymal Stem Cells on Cryopreserved Tracheal Allografts in Rabbits

  • Kim, Hyunjo (Department of Thoracic and Cardiovascular Surgery, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine)
  • Received : 2012.11.26
  • Accepted : 2013.03.07
  • Published : 2013.10.05

Abstract

Background: Ischemic injury and the rejection process are the main reasons for graft failure in tracheal transplantation models. To enhance the acceptance, we investigated the influence of mesenchymal stem cells (MSCs) on tracheal allografts. Methods: Extracted tracheal grafts from New Zealand white rabbits were cryopreserved for 4 weeks and orthotopically transplanted (control group A, n=8). In group B (n=8), cyclosporin A (CsA, 10 mg/kg) was injected daily into the peritoneal cavity. In group C (n=8), MSCs ($1.0{\times}10^7$ cells/kg) from the same donor of the tracheal allograft, which had been pre-cultured for 4 weeks, were infused intravenously after transplantation. In group D (n=8), MSCs were infused and CsA was injected daily. Four weeks after transplantation, gross and histomorphological assessments were conducted for graft necrosis, measuring the cross-sectional area of the allograft, determining the degree of epithelization, lymphocytic infiltration, and vascular regeneration. Results: The morphologic integrity of the trachea was retained completely in all cases. The cross-sectional areas were decreased significantly in group A (p=0.018) and B (p=0.045). The degree of epithelization was enhanced (p=0.012) and the lymphocytic infiltration was decreased (p=0.048) significantly in group D compared to group A. The degree of vascular regeneration did not differ significantly in any of the groups. There were no significant correlations among epithelization, lymphocytic infiltration, and vascular regeneration. Conclusion: The administration of MSCs with concurrent injections of CsA enhanced and promoted epithelization and prevented lymphocytic infiltration in tracheal allografts, allowing for better acceptance of the allograft.

Keywords

References

  1. Okumus A, Cizmeci O, Kabakas F, Kuvat SV, Bilir A, Aydin A. Circumferential trachea reconstruction with a prefabricated axial bio-synthetic flap: experimental study. Int J Pediatr Otorhinolaryngol 2005;69:335-44. https://doi.org/10.1016/j.ijporl.2004.10.005
  2. Goto Y, Noguchi Y, Nomura A, et al. In vitro reconstitution of the tracheal epithelium. Am J Respir Cell Mol Biol 1999;20:312-8. https://doi.org/10.1165/ajrcmb.20.2.3062
  3. Walles T, Giere B, Hofmann M, et al. Experimental generation of a tissue-engineered functional and vascularized trachea. J Thorac Cardiovasc Surg 2004;128:900-6. https://doi.org/10.1016/j.jtcvs.2004.07.036
  4. Delaere PR, Liu ZY, Hermans R, Sciot R, Feenstra L. Experimental tracheal allograft revascularization and transplantation. J Thorac Cardiovasc Surg 1995;110:728-37. https://doi.org/10.1016/S0022-5223(95)70105-2
  5. Genden EM, Gannon PJ, Smith S, Deftereos M, Urken ML. Microvascular transplantation of tracheal allografts model in the canine. Ann Otol Rhinol Laryngol 2003;112:307-13. https://doi.org/10.1177/000348940311200404
  6. Couraud L, Baudet E, Martigne C, et al. Bronchial revascularization in double-lung transplantation: a series of 8 patients. Bordeaux Lung and Heart-Lung Transplant Group. Ann Thorac Surg 1992;53:88-94. https://doi.org/10.1016/0003-4975(92)90764-U
  7. Morgan E, Lima O, Goldberg M, Ferdman A, Luk SK, Cooper JD. Successful revascularization of totally ischemic bronchial autografts with omental pedicle flaps in dogs. J Thorac Cardiovasc Surg 1982;84:204-10.
  8. Khaghani A, Tadjkarimi S, al-Kattan K, et al. Wrapping the anastomosis with omentum or an internal mammary artery pedicle does not improve bronchial healing after single lung transplantation: results of a randomized clinical trial. J Heart Lung Transplant 1994;13:767-73.
  9. Date H, Trulock EP, Arcidi JM, Sundaresan S, Cooper JD, Patterson GA. Improved airway healing after lung transplantation: an analysis of 348 bronchial anastomoses. J Thorac Cardiovasc Surg 1995;110:1424-32. https://doi.org/10.1016/S0022-5223(95)70065-X
  10. Maksoud-Filho JG, Rodrigues CJ, Tannuri U, Maksoud JG. The effects of early and delayed immunosuppression in experimental tracheal transplantation with omentopexy. J Pediatr Surg 1999;34:1223-8. https://doi.org/10.1016/S0022-3468(99)90156-2
  11. Beigel A, Muller-Ruchholtz W. Tracheal transplantation. I. The immunogenic effect of rat tracheal transplants. Arch Otorhinolaryngol 1984;240:185-92.
  12. Beigel A, Muller-Ruchholtz W. Tracheal transplantation. II. Influence of genetic difference and degree of sensitization on reactions to the tracheal transplant. Arch Otorhinolaryngol 1984;240:217-25.
  13. Bujia J, Wilmes E, Hammer C, Kastenbauer E. Tracheal transplantation: demonstration of HLA class II subregion gene products on human trachea. Acta Otolaryngol 1990;110:149-54. https://doi.org/10.3109/00016489009122530
  14. Rossi GA, Sacco O, Balbi B, et al. Human ciliated bronchial epithelial cells: expression of the HLA-DR antigens and of the HLA-DR alpha gene, modulation of the HLA-DR antigens by gamma-interferon and antigen-presenting function in the mixed leukocyte reaction. Am J Respir Cell Mol Biol 1990;3:431-9. https://doi.org/10.1165/ajrcmb/3.5.431
  15. Delaere PR, Liu Z, Sciot R, Welvaart W. The role of immunosuppression in the long-term survival of tracheal allografts. Arch Otolaryngol Head Neck Surg 1996;122:1201-8. https://doi.org/10.1001/archotol.1996.01890230047010
  16. Neuringer IP, Aris RM, Burns KA, Bartolotta TL, Chalermskulrat W, Randell SH. Epithelial kinetics in mouse heterotopic tracheal allografts. Am J Transplant 2002;2:410-9. https://doi.org/10.1034/j.1600-6143.2002.20503.x
  17. Yang J, Hu J, Wu Z. Experimental study on the tracheal allografts with decreased antigenicity. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2006;20:73-6.
  18. Stoelben E, Harpering H, Haberstroh J, di Filippo A, Wellens E. Heterotopic transplantation of cryopreserved tracheae in a rat model. Eur J Cardiothorac Surg 2003;23:15-20. https://doi.org/10.1016/S1010-7940(02)00671-1
  19. Ikonen TS, Brazelton TR, Berry GJ, Shorthouse RS, Morris RE. Epithelial re-growth is associated with inhibition of obliterative airway disease in orthotopic tracheal allografts in non-immunosuppressed rats. Transplantation 2000;70:857-63. https://doi.org/10.1097/00007890-200009270-00002
  20. Tojo T, Kitamura S, Gojo S, Kushibe K, Nezu K, Taniguchi S. Epithelial regeneration and preservation of tracheal cartilage after tracheal replacement with cryopreserved allograft in the rat. J Thorac Cardiovasc Surg 1998;116:624-7. https://doi.org/10.1016/S0022-5223(98)70169-2
  21. Gammie JS, Li S, Kawaharada N, et al. Mixed allogeneic chimerism prevents obstructive airway disease in a rat heterotopic tracheal transplant model. J Heart Lung Transplant 1998;17:801-8.
  22. Nusair S, Or R, Junadi S, Amir G, Breuer R. Simultaneous donor marrow cell transplantation with reduced intensity conditioning prevents tracheal allograft obliteration in a bronchiolitis obliterans murine model. Chest 2005;128:4024-9. https://doi.org/10.1378/chest.128.6.4024
  23. Al-Khaldi A, Al-Sabti H, Galipeau J, Lachapelle K. Therapeutic angiogenesis using autologous bone marrow stromal cells: improved blood flow in a chronic limb ischemia model. Ann Thorac Surg 2003;75:204-9. https://doi.org/10.1016/S0003-4975(02)04291-1
  24. Pham SM, Rao AS, Zeevi A, et al. Effects of donor bone marrow infusion in clinical lung transplantation. Ann Thorac Surg 2000;69:345-50. https://doi.org/10.1016/S0003-4975(99)01471-X
  25. Nakajima J, Ono M, Takeda M, Kawauchi M, Furuse A, Takizawa H. Role of costimulatory molecules on airway epithelial cells acting as alloantigen-presenting cells. Transplant Proc 1997;29:2297-300. https://doi.org/10.1016/S0041-1345(97)00334-5
  26. Boehler A, Chamberlain D, Kesten S, Slutsky AS, Liu M, Keshavjee S. Lymphocytic airway infiltration as a precursor to fibrous obliteration in a rat model of bronchiolitis obliterans. Transplantation 1997;64:311-7. https://doi.org/10.1097/00007890-199707270-00023
  27. Davreux CJ, Chu NH, Waddell TK, Mayer E, Patterson GA. Improved tracheal allograft viability in immunosuppressed rats. Ann Thorac Surg 1993;55:131-4. https://doi.org/10.1016/0003-4975(93)90488-4
  28. Nakanishi R, Yasumoto K. Minimal dose of cyclosporin A for tracheal allografts. Ann Thorac Surg 1995;60:635-9. https://doi.org/10.1016/0003-4975(95)00427-M
  29. King MB, Jessurun J, Savik SK, Murray JJ, Hertz MI. Cyclosporine reduces development of obliterative bronchiolitis in a murine heterotopic airway model. Transplantation 1997;63:528-32. https://doi.org/10.1097/00007890-199702270-00007
  30. Roth-Eichhorn S, Schade I, Kasper M, et al. Anti-proliferative properties of the phosphodiesterase-4 inhibitor rolipram can supplement immunosuppressive effects of cyclosporine for treatment of obliterative bronchiolitis in heterotopic rat allografts. J Heart Lung Transplant 2001;20:1188-98. https://doi.org/10.1016/S1053-2498(01)00340-0
  31. Messineo A, Filler RM, Bahoric A, Smith CR. Repair of long tracheal defects with cryopreserved cartilaginous allografts. J Pediatr Surg 1992;27:1131-4. https://doi.org/10.1016/0022-3468(92)90574-Q
  32. Mukaida T, Shimizu N, Aoe M, et al. Experimental study of tracheal allotransplantation with cryopreserved grafts. J Thorac Cardiovasc Surg 1998;116:262-6. https://doi.org/10.1016/S0022-5223(98)70125-4
  33. Yokomise H, Inui K, Wada H, et al. High-dose irradiation prevents rejection of canine tracheal allografts. J Thorac Cardiovasc Surg 1994;107:1391-7.
  34. LaMuraglia GM, Adili F, Schmitz-Rixen T, Michaud NA, Flotte TJ. Photodynamic therapy inhibits experimental allograft rejection: a novel approach for the development of vascular bioprostheses. Circulation 1995;92:1919-26. https://doi.org/10.1161/01.CIR.92.7.1919
  35. Liu Y, Nakamura T, Yamamoto Y, et al. Immunosuppressant- free allotransplantation of the trachea: the antigenicity of tracheal grafts can be reduced by removing the epithelium and mixed glands from the graft by detergent treatment. J Thorac Cardiovasc Surg 2000;120:108-14. https://doi.org/10.1067/mtc.2000.106655
  36. Tojo T, Niwaya K, Sawabata N, et al. Tracheal replacement with cryopreserved tracheal allograft: experiment in dogs. Ann Thorac Surg 1998;66:209-13. https://doi.org/10.1016/S0003-4975(98)00270-7
  37. Tanaka H, Maeda K, Okita Y. Transplantation of the cryopreserved tracheal allograft in growing rabbits. J Pediatr Surg 2003;38:1707-11. https://doi.org/10.1016/j.jpedsurg.2003.08.036
  38. Moriyama H, Sasajima T, Hirata S, Yamazaki K, Yatsuyanagi E, Kubo Y. Revascularization of canine cryopreserved tracheal allografts. Ann Thorac Surg 2000;69:1701-6. https://doi.org/10.1016/S0003-4975(00)01297-2
  39. Murakawa T, Nakajima J, Motomura N, Murakami A, Takamoto S. Successful allotransplantation of cryopreserved tracheal grafts with preservation of the pars membranacea in nonhuman primates. J Thorac Cardiovasc Surg 2002;123:153-60. https://doi.org/10.1067/mtc.2002.119056
  40. Mukaida T, Shimizu N, Aoe M, Andou A, Date H. Tracheal allotransplantation after varying terms of cryopreservation. Transplant Proc 1998;30:3397-400. https://doi.org/10.1016/S0041-1345(98)01076-8
  41. Cleven HA, Genden EM, Moran TM. Reepithelialized orthotopic tracheal allografts expand memory cytotoxic T lymphocytes but show no evidence of chronic rejection. Transplantation 2005;79:861-8. https://doi.org/10.1097/01.TP.0000157119.39395.C3
  42. Starzl TE, Demetris AJ, Trucco M, et al. Chimerism and donor-specific nonreactivity 27 to 29 years after kidney allotransplantation. Transplantation 1993;55:1272-7. https://doi.org/10.1097/00007890-199306000-00012
  43. Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 2004;95:9-20. https://doi.org/10.1161/01.RES.0000135902.99383.6f
  44. Devine SM, Bartholomew AM, Mahmud N, et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 2001;29:244-55. https://doi.org/10.1016/S0301-472X(00)00635-4
  45. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003;57:11-20. https://doi.org/10.1046/j.1365-3083.2003.01176.x
  46. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002;30:42-8. https://doi.org/10.1016/S0301-472X(01)00769-X

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