Growing a Surrogate Organ in Lymph Node



Currently, the shortage of organs available for transplant into terminally ill patients represents a major worldwide medical, social, and economic challenge. For many years, the transplant of (stem) cells to regenerate failing organs has been proposed as an alternative to whole-organ transplantation. However, orthotopic cell-based therapy directed at a diseased organ may not be feasible for many patients. The efficacy of cell-based therapy becomes questionable in disease states which compromise the environment needed for cellular engraftment and function. This is true in many end stage organ failure scenarios such as cirrhotic or fibrotic liver. In another such example, DiGeorge syndrome patients suffer from an absence of thymic development causing severe immunodeficiency. In this instance, ectopic transplantation of allografted tissue is necessary to replace thymic function. Consequently, a critical component of cell therapy for these patients is the establishment of an optimal in vivo ectopic cell or tissue transplant site to achieve restoration of organ function. We have pioneered use of the lymph node as a site for ectopic tissue and organ development. In this chapter, we will discuss two applications, the transplantation of hepatocytes and thymic tissues in lymph node, to develop functional ectopic organs.


Lymph Node Orthotopic Liver Transplantation Thymic Tissue DiGeorge Syndrome High Endothelial Venule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

List of Abbreviations


Orthotopic liver transplantation


Fumarylacetoacetate hydrolase






splenic injection




cytokeratin 8


cytokeratin 5


Embryonic Stem Cells/Induced Pluripotent Stem Cells



This work was supported by the NIH Grant R01-DK085711. We thank Lynda Guzik for proofreading and editing.


  1. Braun KM, Sandgren EP (2000) Cellular origin of regenerating parenchyma in a mouse model of severe hepatic injury. Am J Pathol 157(2):561–569CrossRefPubMedPubMedCentralGoogle Scholar
  2. Clark RA, Yamanaka K, Bai M, Dowgiert R, Kupper TS (2005) Human skin cells support thymus-independent T cell development. J Clin Invest 115(11):3239–3249CrossRefPubMedPubMedCentralGoogle Scholar
  3. Davies EG (2013) Immunodeficiency in DiGeorge syndrome and options for treating cases with complete athymia. Front Immunol 4:322CrossRefPubMedPubMedCentralGoogle Scholar
  4. DeWard AD, Komori J, Lagasse E (2014) Ectopic transplantation sites for cell-based therapy. Curr Opin Organ Transplant 19(2):169–174CrossRefPubMedPubMedCentralGoogle Scholar
  5. Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC (1998) Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 338(20):1422–1426CrossRefPubMedGoogle Scholar
  6. Francipane MG, Lagasse E (2014) Maturation of embryonic tissues in a lymph node: a new approach for bioengineering complex organs. Organogenesis 10:323–331CrossRefPubMedGoogle Scholar
  7. Francipane MG, Lagasse E (2015a) The lymph node as a new site for kidney organogenesis. Stem Cells Transl Med 4(3):295–307CrossRefPubMedPubMedCentralGoogle Scholar
  8. Francipane MG, Lagasse E (2015b) Pluripotent stem cells to rebuild a kidney: the lymph node as a possible developmental niche. Cell Transplant. PMID: 26160801Google Scholar
  9. Gill J, Malin M, Hollander GA, Boyd R (2002) Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol 3(7):635–642CrossRefPubMedGoogle Scholar
  10. Grompe M (2006) Principles of therapeutic liver repopulation. J Inherit Metab Dis 29(2–3):421–425CrossRefPubMedGoogle Scholar
  11. Grompe M, Lindstedt S, al-Dhalimy M, Kennaway NG, Papaconstantinou J, Torres-Ramos CA, Ou CN, Finegold M (1995) Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nat Genet 10(4):453–460CrossRefPubMedGoogle Scholar
  12. Grompe M, Overturf K, al-Dhalimy M, Finegold M (1998) Therapeutic trials in the murine model of hereditary tyrosinaemia type I: a progress report. J Inherit Metab Dis 21(5):518–531CrossRefPubMedGoogle Scholar
  13. Gupta S, Vemuru RP, Lee CD, Yerneni PR, Aragona E, Burk RD (1994) Hepatocytes exhibit superior transgene expression after transplantation into liver and spleen compared with peritoneal cavity or dorsal fat pad: implications for hepatic gene therapy. Hum Gene Ther 5(8):959–967CrossRefPubMedGoogle Scholar
  14. Henne-Bruns D, Kruger U, Sumpelmann D, Lierse W, Kremer B (1991) Intraperitoneal hepatocyte transplantation: morphological results. Virchows Arch A Pathol Anat Histopathol 419(1):45–50CrossRefPubMedGoogle Scholar
  15. Hoppo T, Komori J, Manohar R, Stolz DB, Lagasse E (2011) Rescue of lethal hepatic failure by hepatized lymph nodes in mice. Gastroenterology 140(2):656–666.e652CrossRefPubMedGoogle Scholar
  16. Komori J, Boone L, DeWard A, Hoppo T, Lagasse E (2012) The mouse lymph node as an ectopic transplantation site for multiple tissues. Nat Biotechnol 30(10):976–983CrossRefPubMedPubMedCentralGoogle Scholar
  17. Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M (2000) Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6(11):1229–1234CrossRefPubMedGoogle Scholar
  18. Lakkis FG, Arakelov A, Konieczny BT, Inoue Y (2000) Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med 6(6):686–688CrossRefPubMedGoogle Scholar
  19. Lipshutz GS, Busuttil RW (2007) Liver transplantation in those of advancing age: the case for transplantation. Liver Transpl 13(10):1355–1357CrossRefPubMedGoogle Scholar
  20. Maillard I, Schwarz BA, Sambandam A, Fang T, Shestova O, Xu L, Bhandoola A, Pear WS (2006) Notch-dependent T-lineage commitment occurs at extrathymic sites following bone marrow transplantation. Blood 107(9):3511–3519CrossRefPubMedPubMedCentralGoogle Scholar
  21. Markert ML, Devlin BH, McCarthy EA (2010) Thymus transplantation. Clin Immunol 135(2):236–246CrossRefPubMedPubMedCentralGoogle Scholar
  22. Overturf K, Al-Dhalimy M, Tanguay R, Brantly M, Ou CN, Finegold M, Grompe M (1996) Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat Genet 12(3):266–273CrossRefPubMedGoogle Scholar
  23. Overturf K, al-Dhalimy M, Ou CN, Finegold M, Grompe M (1997) Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol 151(5):1273–1280PubMedPubMedCentralGoogle Scholar
  24. Parent AV, Russ HA, Khan IS, Laflam TN, Metzger TC, Anderson MS, Hebrok M (2013) Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell 13:219–229CrossRefPubMedGoogle Scholar
  25. Perkins JD, Halldorson JB, Bakthavatsalam R, Fix OK, Carithers RL Jr, Reyes JD (2009) Should liver transplantation in patients with model for end-stage liver disease scores <or= 14 be avoided? A decision analysis approach. Liver Transpl 15(2):242–254CrossRefPubMedGoogle Scholar
  26. Poznansky MC, Evans RH, Foxall RB, Olszak IT, Piascik AH, Hartman KE, Brander C, Meyer TH, Pykett MJ, Chabner KT, Kalams SA, Rosenzweig M, Scadden DT (2000) Efficient generation of human T cells from a tissue-engineered thymic organoid. Nat Biotechnol 18(7):729–734CrossRefPubMedGoogle Scholar
  27. Reuben A (2007) Alcohol and the liver. Curr Opin Gastroenterol 23(3):283–291CrossRefPubMedGoogle Scholar
  28. Rhim JA, Sandgren EP, Degen JL, Palmiter RD, Brinster RL (1994) Replacement of diseased mouse liver by hepatic cell transplantation. Science 263(5150):1149–1152CrossRefPubMedGoogle Scholar
  29. Rodewald HR (2000) Thymus epithelial cell reaggregate grafts. Curr Top Microbiol Immunol 251:101–108PubMedGoogle Scholar
  30. Seach N, Mattesich M, Abberton K, Matsuda K, Tilkorn DJ, Rophael J, Boyd RL, Morrison WA (2010) Vascularized tissue engineering mouse chamber model supports thymopoiesis of ectopic thymus tissue grafts. Tissue Eng Part C Methods 16(3):543–551CrossRefPubMedGoogle Scholar
  31. Smith MK, Mooney DJ (2007) Hypoxia leads to necrotic hepatocyte death. J Biomed Mater Res A 80(3):520–529CrossRefPubMedGoogle Scholar
  32. Starzl TE, Groth CG, Brettschneider L, Penn I, Fulginiti VA, Moon JB, Blanchard H, Martin AJ Jr, Porter KA (1968) Orthotopic homotransplantation of the human liver. Ann Surg 168(3):392–415CrossRefPubMedPubMedCentralGoogle Scholar
  33. Strom SC, Chowdhury JR, Fox IJ (1999) Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis 19(1):39–48CrossRefPubMedGoogle Scholar
  34. Terra R, Louis I, Le Blanc R, Ouellet S, Zuniga-Pflucker JC, Perreault C (2005) T-cell generation by lymph node resident progenitor cells. Blood 106(1):193–200CrossRefPubMedGoogle Scholar
  35. Volk ML, Hernandez JC, Lok AS, Marrero JA (2007) Modified Charlson comorbidity index for predicting survival after liver transplantation. Liver Transpl 13(11):1515–1520CrossRefPubMedGoogle Scholar
  36. von Andrian UH (1996) Intravital microscopy of the peripheral lymph node microcirculation in mice. Microcirculation 3(3):287–300CrossRefGoogle Scholar
  37. Weglarz TC, Degen JL, Sandgren EP (2000) Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes. Am J Pathol 157(6):1963–1974CrossRefPubMedPubMedCentralGoogle Scholar
  38. Weir GC (2012) Cellular transplantation into lymph nodes may not be such a crazy idea. Cell Stem Cell 11(5):587–588CrossRefPubMedGoogle Scholar
  39. Zakrzewski JL, Tuckett AZ, van den Brink MR (2012) Transforming lymph nodes into tissue factories. Nat Biotechnol 30(10):958–959CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  1. 1.McGowan Institute for Regenerative Medicine, Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA

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