Abstract
Cell-based therapy has been viewed as a promising alternative to organ transplantation, but cell transplantation aimed at organ repair is not always possible. Here we show that the mouse lymph node can support the engraftment and growth of healthy cells from multiple tissues. Direct injection of hepatocytes into a single mouse lymph node generated enough ectopic liver mass to rescue the survival of mice with lethal metabolic disease. Furthermore, thymuses transplanted into single lymph nodes of athymic nude mice generated functional immune systems that were capable of rejecting allogeneic and xenogeneic grafts. Additionally, pancreatic islets injected into the lymph nodes of diabetic mice restored normal glucose control. Collectively, these results suggest the practical approach of targeting lymph nodes to restore, maintain or improve tissue and organ functions.
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References
Fisher, R.A. & Strom, S.C. Human hepatocyte transplantation: worldwide results. Transplantation 82, 441–449 (2006).
Shapiro, A.M. et al. International trial of the Edmonton protocol for islet transplantation. N. Engl. J. Med. 355, 1318–1330 (2006).
Schuppan, D. & Afdhal, N.H. Liver cirrhosis. Lancet 371, 838–851 (2008).
Markert, M.L. et al. Transplantation of thymus tissue in complete DiGeorge syndrome. N. Engl. J. Med. 341, 1180–1189 (1999).
Markert, M.L., Devlin, B.H. & McCarthy, E.A. Thymus transplantation. Clin. Immunol. 135, 236–246 (2010).
Merani, S., Toso, C., Emamaullee, J. & Shapiro, A.M. Optimal implantation site for pancreatic islet transplantation. Br. J. Surg. 95, 1449–1461 (2008).
Dhawan, A., Puppi, J., Hughes, R.D. & Mitry, R.R. Human hepatocyte transplantation: current experience and future challenges. Nat. Rev. Gastroenterol. Hepatol. 7, 288–298 (2010).
Cyster, J.G. Chemokines and cell migration in secondary lymphoid organs. Science 286, 2098–2102 (1999).
von Andrian, U.H. & Mempel, T.R. Homing and cellular traffic in lymph nodes. Nat. Rev. Immunol. 3, 867–878 (2003).
Sleeman, J.P. & Thiele, W. Tumor metastasis and the lymphatic vasculature. Int. J. Cancer 125, 2747–2756 (2009).
Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).
Hoppo, T., Komori, J., Manohar, R., Stolz, D.B. & Lagasse, E. Rescue of lethal hepatic failure by hepatized lymph nodes in mice. Gastroenterology 140, 656–666 (2011).
Van den Broeck, W., Derore, A. & Simoens, P. Anatomy and nomenclature of murine lymph nodes: descriptive study and nomenclatory standardization in BALB/cAnNCrl mice. J. Immunol. Methods 312, 12–19 (2006).
Perl, A.K., Wilgenbus, P., Dahl, U., Semb, H. & Christofori, G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392, 190–193 (1998).
Pham, T.H. et al. Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J. Exp. Med. 207, 17–27 (2010).
Grigorova, I.L. et al. Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells. Nat. Immunol. 10, 58–65 (2009).
Shields, J.D. et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11, 526–538 (2007).
Michalopoulos, G.K. & DeFrances, M.C. Liver regeneration. Science 276, 60–66 (1997).
Grompe, M. et al. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nat. Genet. 10, 453–460 (1995).
Overturf, K., al-Dhalimy, M., Ou, C.N., Finegold, M. & Grompe, M. Serial transplantation reveals the stem-cell–like regenerative potential of adult mouse hepatocytes. Am. J. Pathol. 151, 1273–1280 (1997).
Lagasse, E. et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat. Med. 6, 1229–1234 (2000).
Notenboom, R.G., de Boer, P.A., Moorman, A.F. & Lamers, W.H. The establishment of the hepatic architecture is a prerequisite for the development of a lobular pattern of gene expression. Development 122, 321–332 (1996).
Katakai, T., Hara, T., Sugai, M., Gonda, H. & Shimizu, A. Lymph node fibroblastic reticular cells construct the stromal reticulum via contact with lymphocytes. J. Exp. Med. 200, 783–795 (2004).
Gretz, J.E., Anderson, A.O. & Shaw, S. Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol. Rev. 156, 11–24 (1997).
Lakkis, F.G., Arakelov, A., Konieczny, B.T. & Inoue, Y. Immunologic 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat. Med. 6, 686–688 (2000).
Siegler, E.L., Tick, N., Teresky, A.K., Rosenstraus, M. & Levine, A.J. Teratocarcinoma transplantation rejection loci: an H-2–linked tumor rejection locus. Immunogenetics 9, 207–220 (1979).
Dressel, R. et al. The tumorigenicity of mouse embryonic stem cells and in vitro differentiated neuronal cells is controlled by the recipients' immune response. PLoS ONE 3, e2622 (2008).
Bumgardner, G.L., Li, J., Heininger, M. & Orosz, C.G. Costimulation pathways in host immune responses to allogeneic hepatocytes. Transplantation 66, 1841–1845 (1998).
Gao, D., Li, J., Orosz, C.G. & Bumgardner, G.L. Different costimulation signals used by CD4+ and CD8+ cells that independently initiate rejection of allogenic hepatocytes in mice. Hepatology 32, 1018–1028 (2000).
Rodewald, H.R. Thymus organogenesis. Annu. Rev. Immunol. 26, 355–388 (2008).
Pearse, G. Normal structure, function and histology of the thymus. Toxicol. Pathol. 34, 504–514 (2006).
Odoux, C. et al. A stochastic model for cancer stem cell origin in metastatic colon cancer. Cancer Res. 68, 6932–6941 (2008).
Ohashi, K. et al. Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases. Hepatology 41, 132–140 (2005).
Rodeck, B., Kardorff, R., Melter, M., Schlitt, H.J. & Oldhafer, K.J. Auxiliary partial orthotopic liver transplantation for acute liver failure in two children. Pediatr. Transplant. 3, 328–332 (1999).
Sanz-Rodriguez, F. et al. Endoglin regulates cytoskeletal organization through binding to ZRP-1, a member of the Lim family of proteins. J. Biol. Chem. 279, 32858–32868 (2004).
Gerber, S.A. et al. Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am. J. Pathol. 169, 1739–1752 (2006).
Lawenda, B.D., Mondry, T.E. & Johnstone, P.A. Lymphedema: a primer on the identification and management of a chronic condition in oncologic treatment. CA Cancer J. Clin. 59, 8–24 (2009).
Senti, G. et al. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc. Natl. Acad. Sci. USA 105, 17908–17912 (2008).
Kim, M. et al. Ultrasound-guided mesenteric lymph node iohexol injection for thoracic duct computed tomographic lymphography in cats. Vet. Radiol. Ultrasound 52, 302–305 (2011).
Gordon, R.D. & Starzl, T.E. Changing perspectives on liver transplantation in 1988. Clin. Transpl. 5–27 (1988).
Stampfl, D.A. et al. Heterotopic liver transplantation for fulminant Wilson's disease. Gastroenterology 99, 1834–1836 (1990).
Rice, H.E. et al. Thymic transplantation for complete DiGeorge syndrome: medical and surgical considerations. J. Pediatr. Surg. 39, 1607–1615 (2004).
Jiang, J., Wang, H., Madrenas, J. & Zhong, R. Surgical technique for vascularized thymus transplantation in mice. Microsurgery 19, 56–60 (1999).
Robertson, R.P. Islet transplantation as a treatment for diabetes—a work in progress. N. Engl. J. Med. 350, 694–705 (2004).
Harlan, D.M., Kenyon, N.S., Korsgren, O. & Roep, B.O. Current advances and travails in islet transplantation. Diabetes 58, 2175–2184 (2009).
Fiorina, P., Shapiro, A.M., Ricordi, C. & Secchi, A. The clinical impact of islet transplantation. Am. J. Transplant. 8, 1990–1997 (2008).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Zhao, T., Zhang, Z.N., Rong, Z. & Xu, Y. Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215 (2011).
Acknowledgements
We would like to thank S. Thorne and R. Sikorski for the in vivo imaging and the luciferase C57BL/6 transgenic mice. 129sv and 129sv Fah−/− mice were a kind gift from M. Grompe (Oregon Health and Sciences University). CTLA4-Ig and MR1 antibodies were a kind gift from F. Lakkis (University of Pittsburgh). This project used University of Pittsburgh Cancer Institute shared resources that are supported in part by award P30CA047904. This work was supported by the US National Institutes of Health grant R01 DK085711 (J.K., L.B., A.D. and E.L.).
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J.K., L.B. and A.D. performed and analyzed experiments for liver, thymus and pancreatic islets, respectively. T.H. conducted experiments. J.K., L.B., A.D. and E.L. designed experiments and wrote the manuscript. E.L. performed overall project planning and coordination. All authors edited and approved the final manuscript.
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Komori, J., Boone, L., DeWard, A. et al. The mouse lymph node as an ectopic transplantation site for multiple tissues. Nat Biotechnol 30, 976–983 (2012). https://doi.org/10.1038/nbt.2379
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DOI: https://doi.org/10.1038/nbt.2379
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