Abstract
Regenerative medicine aims at producing new cells for repair or replacement of diseased and damaged tissues. Embryonic and adult stem cells have been suggested as attractive sources of cells for generating the new cells needed. The leading dogma was that adult cells in mammals, once committed to a specific lineage, become “terminally differentiated” and can no longer change their fate. However, in recent years increasing evidence has accumulated demonstrating the remarkable ability of some differentiated cells to be converted into a different cell type via a process termed developmental redirection or adult cells reprogramming. For example, abundant human cell types, such as dermal fibroblasts and adipocytes, could potentially be harvested and converted into other, medically important cell types, such as neurons, cardiomyocytes, or pancreatic β cells. In this chapter, we describe a method of activating the pancreatic lineage and β-cells function in adult human liver cells by ectopic expression of pancreatic transcription factors. This approach aims to generate custom-made autologous surrogate β cells for treatment of diabetes, and possibly bypass both the shortage of cadaveric human donor tissues and the need for life-long immune-suppression.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ferber, S., Halkin, A., Cohen, H., Ber, I., Einav, Y., Goldberg, I., Barshack, I., Seijffers, R., Kopolovic, J., Kaiser, N., and Karasik, A. (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med 6, 568–72.
Ber, I., Shternhall, K., Perl, S., Ohanuna, Z., Goldberg, I., Barshack, I., Benvenisti-Zarum, L., Meivar-Levy, I., and Ferber, S. (2003) Functional, persistent, and extended liver to pancreas transdifferentiation. J Biol Chem 278, 31950–7.
Sapir, T., Shternhall, K., Meivar-Levy, I., Blumenfeld, T., Cohen, H., Skutelsky, E., Eventov-Friedman, S., Barshack, I., Goldberg, I., Pri-Chen, S., Ben-Dor, L., Polak-Charcon, S., Karasik, A., Shimon, I., Mor, E., and Ferber, S. (2005) Cell-replacement therapy for diabetes: generating functional insulin-producing tissue from adult human liver cells. Proc Natl Acad Sci U S A 102, 7964–9.
Shternhall-Ron, K., Quintana, F. J., Perl, S., Meivar-Levy, I., Barshack, I., Cohen, I. R., and Ferber, S. (2007) Ectopic PDX-1 expression in liver ameliorates type 1 diabetes. J Autoimmun 28, 134–42.
Meivar-Levy, I., Sapir, T., Gefen-Halevi, S., Aviv, V., Barshack, I., Onaca, N., Mor, E., and Ferber, S. (2007) Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/enhancer-binding protein beta. Hepatology 46, 898–905.
Meivar-Levy, I., and Ferber, S. (2006) Regenerative medicine: using liver to generate pancreas for treating diabetes. Isr Med Assoc J. 8, 430–4.
Meivar-Levy, I., and Ferber, S. (2003) New organs from our own tissues: liver-to-pancreas transdifferentiation. Trends Endocrinol Metab 14, 460–6.
Cao, L. Z., Tang, D. Q., Horb, M. E., Li, S. W., and Yang, L. J. (2004) High glucose is necessary for complete maturation of Pdx1-VP16-expressing hepatic cells into functional insulin-producing cells. Diabetes 53, 3168–78.
Horb, M. E., Shen, C. N., Tosh, D., and Slack, J. M. (2003) Experimental conversion of liver to pancreas. Curr Biol 13, 105–15.
Imai, J., Katagiri, H., Yamada, T., Ishigaki, Y., Ogihara, T., Uno, K., Hasegawa, Y., Gao, J., Ishihara, H., Sasano, H., Mizuguchi, H., Asano, T., and Oka, Y. (2005) Constitutively active PDX1 induced efficient insulin production in adult murine liver. Biochem Biophys Res Commun 326, 402–9.
Kaneto, H., Matsuoka, T. A., Nakatani, Y., Miyatsuka, T., Matsuhisa, M., Hori, M., and Yamasaki, Y. (2005) A crucial role of MafA as a novel therapeutic target for diabetes. J Biol Chem 280, 15047–52.
Kaneto, H., Nakatani, Y., Miyatsuka, T., Matsuoka, T. A., Matsuhisa, M., Hori, M., and Yamasaki, Y. (2005) PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. Diabetes 54, 1009–22.
Kojima, H., Fujimiya, M., Matsumura, K., Younan, P., Imaeda, H., Maeda, M., and Chan, L. (2003) NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med 9, 596–603.
Li, W. C., Horb, M. E., Tosh, D., and Slack, J. M. (2005) In vitro transdifferentiation of hepatoma cells into functional pancreatic cells. Mech Dev 122, 835–47.
Miyatsuka, T., Kaneto, H., Kajimoto, Y., Hirota, S., Arakawa, Y., Fujitani, Y., Umayahara, Y., Watada, H., Yamasaki, Y., Magnuson, M. A., Miyazaki, J., and Hori, M. (2003) Ectopically expressed PDX-1 in liver initiates endocrine and exocrine pancreas differentiation but causes dysmorphogenesis. Biochem Biophys Res Commun 310, 1017–25.
Zalzman, M., Gupta, S., Giri, R. K., Berkovich, I., Sappal, B. S., Karnieli, O., Zern, M. A., Fleischer, N., and Efrat, S. (2003) Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. Proc Natl Acad Sci U S A 100, 7253–8.
Muniappan, L., and Ozcan, S. (2007) Induction of insulin secretion in engineered liver cells by nitric oxide. BMC Physiol 7, 11.
Jin, C. X., Li, W. L., Xu, F., Geng, Z. H., He, Z. Y., Su, J., Tao, X. R., Ding, X. Y., Wang, X., and Hu, Y. P. (2008) Conversion of immortal liver progenitor cells into pancreatic endocrine progenitor cells by persistent expression of Pdx-1. J Cell Biochem 104(1), 224–36.
Wang, A. Y., Ehrhardt, A., Xu, H., and Kay, M. A. (2007) Adenovirus transduction is required for the correction of diabetes using Pdx-1 or Neurogenin-3 in the liver. Mol Ther 15, 255–63.
Yatoh, S., Akashi, T., Chan, P. P., Kaneto, H., Sharma, A., Bonner-Weir, S., and Weir, G. C. (2007) NeuroD and reaggregation induce beta-cell specific gene expression in cultured hepatocytes. Diabetes Metab Res Rev 23(3), 239–49
Yamada, S., Yamamoto, Y., Nagasawa, M., Hara, A., Kodera, T., and Kojima, I. (2006) In vitro transdifferentiation of mature hepatocytes into insulin-producing cells. Endocr J 53, 789–95.
Fodor, A., Harel, C., Fodor, L., Armoni, M., Salmon, P., Trono, D., and Karnieli, E. (2007) Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach. Diabetologia 50, 121–30.
Song, Y. D., Lee, E. J., Yashar, P., Pfaff, L. E., Kim, S. Y., and Jameson, J. L. (2007) Islet cell differentiation in liver by combinatorial expression of transcription factors neurogenin-3, BETA2, and RIPE3b1. Biochem Biophys Res Commun 354, 334–9.
Tang, D. Q., Cao, L. Z., Chou, W., Shun, L., Farag, C., Atkinson, M. A., Li, S. W., Chang, L. J., and Yang, L. J. (2006) Role of Pax4 in Pdx1-VP16-mediated liver-to-endocrine pancreas transdifferentiation. Lab Invest 86, 829–41.
Tang, D. Q., Lu, S., Sun, Y. P., Rodrigues, E., Chou, W., Yang, C., Cao, L. Z., Chang, L. J., and Yang, L. J. (2006) Reprogramming liver-stem WB cells into functional insulin-producing cells by persistent expression of Pdx1- and Pdx1-VP16 mediated by lentiviral vectors. Lab Invest 86, 83–93.
Zalzman, M., Anker-Kitai, L., and Efrat, S. (2005) Differentiation of human liver-derived, insulin-producing cells toward the beta-cell phenotype. Diabetes 54, 2568–75.
Koizumi, M., Doi, R., Toyoda, E., Tulachan, S. S., Kami, K., Mori, T., Ito, D., Kawaguchi, Y., Fujimoto, K., Gittes, G. K., and Imamura, M. (2004) Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver. Surgery 136, 449–57.
Nakajima-Nagata, N., Sakurai, T., Mitaka, T., Katakai, T., Yamato, E., Miyazaki, J., Tabata, Y., Sugai, M., and Shimizu, A. (2004) In vitro induction of adult hepatic progenitor cells into insulin-producing cells. Biochem Biophys Res Commun 318, 625–30.
Ferber, S. (2000) Can we create new organs from our own tissues? Isr Med Assoc J 2, 32–6.
Tang, D. Q., Cao, L. Z., Chou, W., Shun, L., Farag, C., Atkinson, M. A., Li, S. W., Chang, L. J., Yang, L. J., Lu, S., Sun, Y. P., Rodrigues, E., and Yang, C. (2006) Role of Pax4 in Pdx1-VP16-mediated liver-to-endocrine pancreas transdifferentiation. Lab Invest 86, 829–41.
Breyer, B., Jiang, W., Cheng, H., Zhou, L., Paul, R., Feng, T., and He, T. C. (2001) Adenoviral vector-mediated gene transfer for human gene therapy. Curr Gene Ther 1, 149–62.
Lai, C. M., Lai, Y. K., and Rakoczy, P. E. (2002) Adenovirus and adeno-associated virus vectors. DNA Cell Biol 21, 895–913.
Vorburger, S. A., and Hunt, K. K. (2002) Adenoviral gene therapy.Oncologist 7, 46–59.
Becker, T. C., Noel, R. J., Coats, W. S., Gomez-Foix, A. M., Alam, T., Gerard, R. D., and Newgard, C. B. (1994) Use of recombinant adenovirus for metabolic engineering of mammalian cells. Methods Cell Biol 43, 161-89.
He, T. C., Zhou, S., da Costa, L. T., Yu, J., Kinzler, K. W., and Vogelstein, B. (1998) A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci U S A 95, 2509–14.
Morral, N., O’Neal, W., Rice, K., Leland, M., Kaplan, J., Piedra, P. A., Zhou, H., Parks, R. J., Velji, R., Aguilar-Cordova, E., Wadsworth, S., Graham, F. L., Kochanek, S., Carey, K. D., and Beaudet, A. L. (1999) Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proc Natl Acad Sci U S A 96, 12816–21.
LaBarre, D. D., and Lowy, R. J. (2001) Improvements in methods for calculating virus titer estimates from TCID50 and plaque assays. J Virol Methods 96, 107–26.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Meivar-Levy, I., Ferber, S. (2010). Adult Cell Fate Reprogramming: Converting Liver to Pancreas. In: Ding, S. (eds) Cellular Programming and Reprogramming. Methods in Molecular Biology, vol 636. Humana Press. https://doi.org/10.1007/978-1-60761-691-7_16
Download citation
DOI: https://doi.org/10.1007/978-1-60761-691-7_16
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-60761-690-0
Online ISBN: 978-1-60761-691-7
eBook Packages: Springer Protocols