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Regenerative Therapies-Trachea

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Regenerative Medicine

Abstract

No preferred treatment, which could offer a functional solution, has been so far developed for patients affected by extensive airway damages. As the field of tissue engineering attempts to develop tracheal replacements, multiple types and combinations of cells, scaffold materials, and/or culture conditions have been used. Interest has been evoked by decellularized natural matrices, which affecting cell proliferation, migration and differentiation, could play an active part in tissue regeneration and remodeling. Using the detergent-enzymatic method, we were able to obtain decellularized human tracheal matrices lacking MHC antigens (bypassing rejection), having structural, mechanical and in vivo pro-angiogenic properties similar to that of native airways and supporting in vivo recellularization. Starting from these results, we have developed an in vivo tissue engineered strategy, based on airway bioengineered grafts combined with autologous stem cells and pharmacological intervention (to boost progenitor cell recruitment commitment), which resulted to be a clinically successful alternative for patients with serious airway disorders.

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Abbreviations

DEM:

detergent-enzymatic method

EPO:

erythropoietin

G-CSF:

granulocyte colony-stimulating factor

MSCs:

marrow stromal cells

TGF-β:

transforming growth factor-β

TNF-α:

tumour necrosis factor-α

β-FGF:

basic fibroblast growth factor

References

  • Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB (2006) Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 367:1241–1246

    Article  PubMed  Google Scholar 

  • Augello A, De Bari C (2010) The regulation of differentiation in mesenchymal stem cells. Hum Gene Ther 21(10):1226–1238

    Article  PubMed  CAS  Google Scholar 

  • Bader A, Macchiarini P (2010) Moving towards in situ tracheal regeneration: the bionic tissue engineered transplantation approach. J Cell Mol Med 14(7):1877–1889

    Article  PubMed  CAS  Google Scholar 

  • Baiguera S, Macchiarini P (2011) Trachea. In: Steinhoff G (ed) Regenerative medicine – from protocol to patient, 1st edn. Springer, London, pp 691–711

    Chapter  Google Scholar 

  • Baiguera S, Jungebluth P, Burns A, Mavilia C, Haag J, De Coppi P, Macchiarini P (2010) Tissue engineered human tracheas for in vivo implantation. Biomaterials 31(34):8931–8938

    Article  PubMed  CAS  Google Scholar 

  • Baiguera S, Del Gaudio C, Jaus MO, Polizzi L, Gonfiotti A, Comin CE, Bianco A, Ribatti D, Taylor DA, Macchiarini P (2012) Long-term changes to in vitro preserved bioengineered human trachea and their implications for decellularized tissues. Biomaterials 33(14):3662–3672. doi:10.1016/j.biomaterials.2012.01.064

    Article  PubMed  CAS  Google Scholar 

  • Barbero A, Ploegert S, Heberer M, Martin I (2003) Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum 48:1315–1325

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharyya N (2004) Contemporary staging and prognosis for primary tracheal malignancies: a population-based analysis. Otolaryngol Head Neck Surg 131:639–642

    Article  PubMed  Google Scholar 

  • Bianchi G, Banfi A, Mastrogiacomo M, Notaro R, Luzzatto L, Cancedda R, Quarto R (2003) Ex vivo enrichment of mesenchymal cell progenitors by fibroblast growth factor 2. Exp Cell Res 287:98–105

    Article  PubMed  CAS  Google Scholar 

  • Brines M (2010) The therapeutic potential of erythropoiesis-stimulating agents for tissue protection: a tale of two receptors. Blood Purif 29(2):86–92

    Article  PubMed  CAS  Google Scholar 

  • Brines M, Cerami A (2008) Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Intern Med 264(5):405–432

    Article  PubMed  CAS  Google Scholar 

  • Bujia J, Pitzke P, Krombach F, Hammer C, Wilmes E, Herberhold C, Kastenbauer E (1991) Immunological behavior of preserved human tracheal allografts: immunological monitoring of a human tracheal recipient. Clin Transplant 5:376–380

    Google Scholar 

  • Cals FL, Hellingman CA, Koevoet W, Baatenburg de Jong RJ, van Osch GJ (2011) Effects of transforming growth factor-β subtypes on in vitro cartilage production and mineralization of human bone marrow stromal-derived mesenchymal stem cells. J Tissue Eng Regen Med 6(1):68–76. doi:10.1002/term.399

    Article  PubMed  Google Scholar 

  • Cardoso WV, Lü J (2006) Regulation of early lung morphogenesis: questions, facts and controversies. Development 133(9):1611–1624

    Article  PubMed  CAS  Google Scholar 

  • Chao MW, Smith JG, Laidlaw C, Joon DL, Ball D (1998) Results of treating primary tumors of the trachea with radiotherapy. Int J Radiat Oncol Biol Phys 41:779–785

    Article  PubMed  CAS  Google Scholar 

  • Choi NC (2004) Radiation therapy in the management of tracheal cancer. In: Grillo HC (ed) Surgery of the trachea and bronchi. BC Decker, Hamilton/London, pp 791–802

    Google Scholar 

  • Delaere P, Vranckx J, Verleden G, De Leyn P, Van Raemdonck D, Leuven Tracheal Transplant Group (2010) Tracheal allotransplantation after withdrawal of immunosuppressive therapy. N Engl J Med 362:138–145

    Article  PubMed  CAS  Google Scholar 

  • Doss AE, Dunn SS, Kucera KA, Clemson LA, Zwischenberger JB (2007) Tracheal replacements: part 2. ASAIO J 53(5):631–639

    Article  PubMed  Google Scholar 

  • Elliott MJ, Haw MP, Jacobs JP, Bailey CM, Evans JN, Herberhold C (1996) Tracheal reconstruction in children using cadaveric homograft trachea. Eur J Cardiothorac Surg 10:707–712

    Article  PubMed  CAS  Google Scholar 

  • Fuchs JR, Terada S, Ochoa ER, Vacanti JP, Fauza DO (2002) Fetal tissue engineering: in utero tracheal augmentation in an ovine model. J Pediatr Surg 37(7):1000–1006

    Article  PubMed  Google Scholar 

  • Gelder CM, Hetzel MR (1993) Primary tracheal tumours: a national survey. Thorax 48:688–692

    Article  PubMed  CAS  Google Scholar 

  • Go T, Jungebluth P, Baiguera S, Asnaghi A, Martorell J, Ostertag H, Mantero S, Birchall M, Bader A, Macchiarini P (2010) Both epithelial cells and mesenchymal stem cell-derived chondrocytes contribute to the survival of tissue-engineered airway transplants in pigs. J Thorac Cardiovasc Surg 139(2):437–443

    Article  PubMed  CAS  Google Scholar 

  • Grillo HC (2002) Tracheal replacement: a critical review. Ann Thorac Surg 73(6):1995–2004

    Article  PubMed  Google Scholar 

  • Grillo HC, Donahue DM, Mathisen DJ, Wain JC, Wright CD (1995) Postintubation tracheal stenosis. Treatment and result. J Thorac Cardiovasc Surg 109(3):486–492

    Article  PubMed  CAS  Google Scholar 

  • Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Rosa-Pimentel E, Sommarin Y, Wendel M, Oldberg A, HeinegÃ¥rd D (1992) Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage. J Biol Chem 267:6132–6136

    PubMed  CAS  Google Scholar 

  • Honings J, Gaissert HA, van der Heijden HF, Verhagen AF, Kaanders JH, Marres HA (2010) Clinical aspects and treatment of primary tracheal malignancies. Acta Otolaryngol 130:763–772

    Article  PubMed  Google Scholar 

  • http://abcnews.go.com/Health/Health/successful-stem-cell-trachea-transplant/story?id=11308383

  • Jacobs JP, Elliott MJ, Haw MP, Bailey CM, Herberhold C (1996) Pediatric tracheal homograft reconstruction: a novel approach to complex tracheal stenosis in children. J Thorac Cardiovasc Surg 112:1549–1560

    Article  PubMed  CAS  Google Scholar 

  • Jacobs JP, Quintessenza JA, Andrews T, Burke RP, Spektor Z, Delius RE, Smith RJ, Elliott MJ, Herberhold C (1999) Tracheal allograft reconstruction: the total North American and worldwide pediatric experiences. Ann Thorac Surg 68:1043–1052

    Article  PubMed  CAS  Google Scholar 

  • Johnstone B, Hering TM, Caplan AI, Goldberg VM, Yoo JU (1998) In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res 238(1):265–272

    Article  PubMed  CAS  Google Scholar 

  • Jungebluth P, Go T, Asnaghi A, Bellini S, Martorell J, Calore C, Urbani L, Ostertag H, Mantero S, Conconi MT, Macchiarini P (2009) Structural and morphologic evaluation of a novel detergent-enzymatic tissue-engineered tracheal tubular matrix. J Thorac Cardiovasc Surg 138(3):586–593

    Article  PubMed  CAS  Google Scholar 

  • Jungebluth P, Alici E, Baiguera S, Blanc KL, Blomberg P, Bozoky B, Crowley C, Einarsson O, Grinnemo KH, Gudbjartsson T, Guyader SL, Henriksson G, Hermanson O, Juto JE, Leidner B, Lilja T, Liska J, Luedde T, Lundin V, Moll G, Nilsson B, Roderburg C, Stromblad S, Sutlu T, Teixeira AI, Watz E, Seifalian A, Macchiarini P (2011) Tracheobronchial transplantation using a stem cell-seeded bioartificial nanocomposite. Lancet 378(9808):1997–2004

    Article  PubMed  CAS  Google Scholar 

  • Jungebluth P, Moll G, Baiguera S, Macchiarini P (2012) Tissue engineered airway: a regenerative solution. Clin Pharmacol Ther 91(1):81–93

    Article  PubMed  CAS  Google Scholar 

  • Kafienah W, Mistry S, Williams C, Hollander AP (2006) Nucleostemin is a marker of proliferating stromal stem cells in adult human bone marrow. Stem Cells 24:1113–1120

    Article  PubMed  Google Scholar 

  • Kafienah W, Mistry S, Dickinson SC, Sims TJ, Learmonth I, Hollander AP (2007) Three-dimensional cartilage tissue engineering using adult stem cells from osteoarthritis patients. Arthritis Rheum 56:177–187

    Article  PubMed  Google Scholar 

  • Kalathur M, Baiguera S, Macchiarini P (2010) Translating tissue-engineered tracheal replacement from bench to bedside. Cell Mol Life Sci 67(24):4185–4196

    Article  PubMed  CAS  Google Scholar 

  • Kanemaru S, Hirano S, Umeda H, Yamashita M, Suehiro A, Nakamura T, Maetani T, Omori K, Ito J (2010) A tissue-engineering approach for stenosis of the trachea and/or cricoid. Acta Otolaryngol Suppl 563:79–83

    Article  PubMed  CAS  Google Scholar 

  • Kanzaki M, Yamato M, Hatakeyama H, Kohno C, Yang J, Umemoto T, Kikuchi A, Okano T, Onuki T (2006) Tissue engineered epithelial cell sheets for the creation of a bioartificial trachea. Tissue Eng 12:1275–1283

    Article  PubMed  Google Scholar 

  • Kojima K, Bonassar LJ, Roy AK, Vacanti CA, Cortiella J (2002) Autologous tissue-engineered trachea with sheep nasal chondrocytes. J Thorac Cardiovasc Surg 123:1177–1184

    Article  PubMed  Google Scholar 

  • Licht PB, Friis S, Pettersson G (2001) Tracheal cancer in Denmark: a nationwide study. Eur J Cardiothorac Surg 19:339–3345

    Article  PubMed  CAS  Google Scholar 

  • Macchiarini P (2006) Primary tracheal tumours. Lancet Oncol 7:83–91

    Article  PubMed  Google Scholar 

  • Macchiarini P, Jungebluth P, Go T, Asnaghi MA, Rees LE, Cogan TA, Dodson A, Martorell J, Bellini S, Parnigotto PP, Dickinson SC, Hollander AP, Mantero S, Conconi MT, Birchall MA (2008) Clinical transplantation of a tissue-engineered airway. Lancet 372:2023–2030

    Article  PubMed  Google Scholar 

  • Marquez-Curtis LA, Turner AR, Sridharan S, Ratajczak MZ, Janowska-Wieczorek A (2011) The ins and outs of hematopoietic stem cells: studies to improve transplantation outcomes. Stem Cell Rev 7:590–607

    Article  PubMed  Google Scholar 

  • Martinod E, Radu DM, Chouahnia K, Seguin A, Fialaire-Legendre A, Brillet PY, Destable MD, Sebbane G, Beloucif S, Valeyre D, Baillard C, Carpentier A (2011) Human transplantation of a biologic airway substitute in conservative lung cancer surgery. Ann Thorac Surg 91(3):837–842

    Article  PubMed  Google Scholar 

  • Mason C, Dunnill P (2008) A brief definition of regenerative medicine. Regen Med 3(1):1–5

    Article  PubMed  Google Scholar 

  • Mastrogiacomo M, Cancedda R, Quarto R (2001) Effect of different growth factors on the chondrogenic potential of human bone marrow stromal cells. Osteoarthritis Cartilage 9(Suppl A):S36–S40

    Article  PubMed  Google Scholar 

  • Meezan E, Hjelle JT, Brendel K (1975) A simple, versatile, nondisruptive method for the isolation of morphologically and chemically pure basement membranes from several tissues. Life Sci 17:1721–1732

    Article  PubMed  CAS  Google Scholar 

  • Mercer RR, Russell ML, Roggli VL, Crapo JD (1994) Cell number and distribution in human and rat airways. Am J Respir Cell Mol Biol 10:613–624

    PubMed  CAS  Google Scholar 

  • Mertsching H, Walles T, Hofmann M, Schanz J, Knapp WH (2005) Engineering of a vascularized scaffold for artificial tissue and organ generation. Biomaterials 33:6610–6617

    Article  Google Scholar 

  • Moroni L, Curti M, Welti M, Korom S, Weder W, de Wijn JR, van Blitterswijk CA (2007) Anatomical 3D fiber-deposited scaffolds for tissue engineering: designing a neotrachea. Tissue Eng 13:2483–2493

    Article  PubMed  CAS  Google Scholar 

  • Mulliken JB, Grillo HC (1968) The limits of tracheal resection with primary anastomosis: further anatomical studies in man. J Thorac Cardiovasc Surg 55(3):418–421

    PubMed  CAS  Google Scholar 

  • Nakamura T, Sato T, Araki M (2009) In situ tissue engineering for tracheal reconstruction using a luminar remodeling type of artificial trachea. J Thorac Cardiovasc Surg 138(4):811–819

    Article  PubMed  Google Scholar 

  • Nehrer S, Spector M, Minas T (1999) Histologic analysis of tissue after failed cartilage repair procedures. Clin Orthop Relat Res 365:149–162

    Article  PubMed  Google Scholar 

  • Nouraei SAR, Nouraei SM, Howard DJ, Sandhu GS (2007) Estimating the population incidence of adult post-intubation laryngotracheal stenosis. Clin Otolaryngol 32:407–409

    Article  PubMed  CAS  Google Scholar 

  • Okubo T, Knoepfler PS, Eisenman RN, Hogan BL (2005) Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation. Development 132(6):1363–1374

    Article  PubMed  CAS  Google Scholar 

  • Omori K, Nakamura T, Kanemaru S, Asato R, Yamashita M, Tanaka S, Magrufov A, Ito J, Shimizu Y (2005) Regenerative medicine of the trachea: the first human case. Ann Otol Rhinol Laryngol 114(6):429–433

    PubMed  Google Scholar 

  • Omori K, Tada Y, Suzuki T, Nomoto Y, Matsuzuka T, Kobayashi K, Nakamura T, Kanemaru S, Yamashita M, Asato R (2008) Clinical application of in situ tissue engineering using a scaffolding technique for reconstruction of the larynx and trachea. Ann Otol Rhinol Laryngol 117(9):673–678

    PubMed  Google Scholar 

  • Osada H (2006) Artificial trachea. J Broncho 13:39–43

    Article  Google Scholar 

  • Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA (2008) Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 14:213–221

    Article  PubMed  CAS  Google Scholar 

  • Petersen TH, Calle EA, Zhao L, Lee EJ, Gui L, Raredon MB, Gavrilov K, Yi T, Zhuang ZW, Breuer C, Herzog E, Niklason LE (2010) Tissue-engineered lungs for in vivo implantation. Science 329:538–541

    Article  PubMed  CAS  Google Scholar 

  • Rock JR, Randell SH, Hogan BL (2010) Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Dis Model Mech 3(9–10):545–556

    Article  PubMed  CAS  Google Scholar 

  • Ronzière MC, Perrier E, Mallein-Gerin F, Freyria AM (2010) Chondrogenic potential of bone marrow- and adipose tissue-derived adult human mesenchymal stem cells. Biomed Mater Eng 20(3):145–158

    PubMed  Google Scholar 

  • Singer NG, Caplan AI (2011) Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol 6:457–478

    Article  PubMed  CAS  Google Scholar 

  • Solchaga LA, Penick K, Porter JD, Goldberg VM, Caplan AI, Welter JF (2005) FGF-2 enhances the mitotic and chondrogenic potentials of human adult bone marrow-derived mesenchymal stem cells. J Cell Physiol 203:398–409

    Article  PubMed  CAS  Google Scholar 

  • Song JJ, Kim SS, Liu Z, Madsen JC, Mathisen DJ, Vacanti JP, Ott HC (2011) Enhanced in vivo function of bioartificial lungs in rats. Ann Thorac Surg 92:998–1005

    Article  PubMed  Google Scholar 

  • Takeyama K, Ohto H (2004) PBSC mobilization. Transfus Apher Sci 31(3):233–243

    Article  PubMed  Google Scholar 

  • Tang QO, Shakib K, Heliotis M, Tsiridis E, Mantalaris A, Ripamonti U, Tsiridis E (2009) TGF-beta3: a potential biological therapy for enhancing chondrogenesis. Expert Opin Biol Ther 9(6):689–701

    Article  PubMed  CAS  Google Scholar 

  • Teramachi M, Nakamura T, Yamamoto Y, Kiyotani T, Takimoto Y, Shimizu Y (1997) Porous-type tracheal prosthesis sealed with collagen sponge. Ann Thorac Surg 64:965–969

    Article  PubMed  CAS  Google Scholar 

  • Tsutsumi S, Shimazu A, Miyazaki K, Pan H, Koike C, Yoshida E, Takagishi K, Kato Y (2001) Retention of multilineage differentiation potential of mesenchymal cells during proliferation in response to FGF. Biochem Biophys Res Commun 288:413–419

    Article  PubMed  CAS  Google Scholar 

  • Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman C, Milwid J, Kobayashi N, Tilles A, Berthiaume F, Hertl M, Nahmias Y, Yarmush ML, Uygun K et al (2010) Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 16:814–820

    Article  PubMed  CAS  Google Scholar 

  • von der Mark K, Gauss V, von der Mark H, Müller P (1977) Relationship between cell shape and type of collagen synthesised as chondrocytes lose their cartilage phenotype in culture. Nature 267(5611):531–532

    Article  PubMed  Google Scholar 

  • Walles T (2004) Bioartificial tracheal grafts: can tissue engineering keep its promise? Expert Rev Med Devices 1(2):241–250

    Article  PubMed  Google Scholar 

  • Walles T, Giere B, Hofmann M, Schanz J, Hofmann F, Mertsching H, Macchiarini P (2004a) Experimental generation of a tissue-engineered functional and vascularized trachea. J Thorac Cardiovasc Surg 128(6):900–906

    PubMed  Google Scholar 

  • Walles T, Giere B, Macchiarini P, Mertsching H (2004b) Expansion of chondrocytes in a three-dimensional matrix for tracheal tissue engineering. Ann Thorac Surg 78:444–448

    Article  PubMed  Google Scholar 

  • Wu W, Cheng X, Zhao Y, Chen F, Feng X, Mao T (2007) Tissue engineering of trachea-like cartilage grafts by using chondrocyte macroaggregate: experimental study in rabbits. Artif Organs 31(11):826–834

    Article  PubMed  Google Scholar 

  • Wurtz A (2010) Tracheal replacement with banked cryopreserved aortic allograft. Ann Thorac Surg 89(6):2072

    Article  PubMed  Google Scholar 

  • Wurtz A, Porte H, Conti M, Desbordes J, Copin MC, Azorin J, Martinod E, Marquette CH (2006) Tracheal replacement with aortic allografts. N Engl J Med 355(18):1938–1940

    Article  PubMed  CAS  Google Scholar 

  • Wurtz A, Porte H, Conti M, Dusson C, Desbordes J, Copin MC, Marquette CH (2010) Surgical technique and results of tracheal and carinal replacement with aortic allografts for salivary gland-type carcinoma. J Thorac Cardiovasc Surg 140(2):387–393

    Article  PubMed  Google Scholar 

  • Yamashita M, Kanemaru S, Hirano S, Magrufov A, Tamaki H, Tamura Y, Kishimoto M, Omori K, Nakamura T, Ito J (2007) Tracheal regeneration after partial resection: a tissue engineering approach. Laryngoscope 117:497–502

    Article  PubMed  Google Scholar 

  • Yang KY, Chen YM, Huang MH, Perng RP (1997) Revisit of primary malignant neoplasms of the trachea: clinical characteristics and survival analysis. Jpn J Clin Oncol 27:305–309

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Paolo Macchiarini M.D., Ph.D. .

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Baiguera, S., Macchiarini, P. (2013). Regenerative Therapies-Trachea. In: Steinhoff, G. (eds) Regenerative Medicine. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5690-8_33

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