Abstract
Changes in cell identity occur in adult mammalian organisms but are rare and often linked to disease. Research in the last few decades has thrown light on how to manipulate cell fate, but the conversion of a particular cell type into another within a living organism (also termed in vivo transdifferentiation) has only been recently achieved in a limited number of tissues. Although the therapeutic promise of this strategy for tissue regeneration and repair is exciting, important efficacy and safety concerns will need to be addressed before it becomes a reality in the clinical practice. Here, we review the most relevant in vivo transdifferentiation studies in adult mammalian animal models, offering a critical assessment of this potentially powerful strategy for regenerative medicine.
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References
Graf, T. (2011). Historical origins of transdifferentiation and reprogramming. Cell Stem Cell, 9(6), 504–16.
Slack, J. M. (2007). Metaplasia and transdifferentiation: from pure biology to the clinic. Nature Reviews Molecular Cell Biology, 8(5), 369–78.
Davis, R. L., Weintraub, H., & Lassar, A. B. (1987). Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell, 51(6), 987–1000.
Weintraub, H., Tapscott, S. J., Davis, R. L., et al. (1989). Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proceedings of the National Academy of Sciences of the United States of America, 86(14), 5434–8.
Schneuwly, S., Klemenz, R., & Gehring, W. J. (1987). Redesigning the body plan of Drosophila by ectopic expression of the homoeotic gene Antennapedia. Nature, 325(6107), 816–8.
Murry, C. E., Kay, M. A., Bartosek, T., Hauschka, S. D., & Schwartz, S. M. (1996). Muscle differentiation during repair of myocardial necrosis in rats via gene transfer with MyoD. Journal of Clinical Investigation, 98(10), 2209–17.
Ferber, S., Halkin, A., Cohen, H., et al. (2000). Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nature Medicine, 6(5), 568–72.
Zhou, Q., Brown, J., Kanarek, A., Rajagopal, J., & Melton, D. A. (2008). In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature, 455(7213), 627–32.
Barrett, N. R. (1957). The lower esophagus lined by columnar epithelium. Surgery, 41(6), 881–94.
Spechler, S. J. (2002). Clinical practice. Barrett’s Esophagus. New England Journal of Medicine, 346(11), 836–42.
Hay, E. D., & Zuk, A. (1995). Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. American Journal of Kidney Diseases, 26(4), 678–90.
Tsukamoto, H., She, H., Hazra, S., Cheng, J., & Miyahara, T. (2006). Anti-adipogenic regulation underlies hepatic stellate cell transdifferentiation. Journal of Gastroenterology and Hepatology, 21(Suppl 3), S102–5.
Li, Y., & Huard, J. (2002). Differentiation of muscle-derived cells into myofibroblasts in injured skeletal muscle. American Journal of Pathology, 161(3), 895–907.
He, J., Lu, H., Zou, Q., & Luo, L. (2014). Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology, 146(3), 789–800 e8.
Zhang, R., Han, P., Yang, H., et al. (2013). In vivo cardiac reprogramming contributes to zebrafish heart regeneration. Nature, 498(7455), 497–501.
Suetsugu-Maki, R., Maki, N., Nakamura, K., et al. (2012). Lens regeneration in axolotl: new evidence of developmental plasticity. BMC Biology, 10, 103.
Wang, T., Chai, R., Kim, G. S., et al. (2015). Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Nature Communications, 6, 6613.
Ber, I., Shternhall, K., Perl, S., et al. (2003). Functional, persistent, and extended liver to pancreas transdifferentiation. Journal of Biological Chemistry, 278(34), 31950–7.
Miyatsuka, T., Kaneto, H., Kajimoto, Y., et al. (2003). Ectopically expressed PDX-1 in liver initiates endocrine and exocrine pancreas differentiation but causes dysmorphogenesis. Biochemical and Biophysical Research Communications, 310(3), 1017–25.
Kojima, H., Fujimiya, M., Matsumura, K., et al. (2003). NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nature Medicine, 9(5), 596–603.
Kaneto, H., Nakatani, Y., Miyatsuka, T., et al. (2005). PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. Diabetes, 54(4), 1009–22.
Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–76.
Yechoor, V., Liu, V., Espiritu, C., et al. (2009). Neurogenin3 is sufficient for transdetermination of hepatic progenitor cells into neo-islets in vivo but not transdifferentiation of hepatocytes. Developmental Cell, 16(3), 358–73.
Banga, A., Akinci, E., Greder, L. V., Dutton, J. R., & Slack, J. M. (2012). In vivo reprogramming of Sox9+ cells in the liver to insulin-secreting ducts. Proceedings of the National Academy of Sciences of the United States of America, 109(38), 15336–41.
Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151), 313–7.
Hartman, Z. C., Appledorn, D. M., & Amalfitano, A. (2008). Adenovirus vector induced innate immune responses: impact upon efficacy and toxicity in gene therapy and vaccine applications. Virus Research, 132(1–2), 1–14.
Mozaffarian, D., Benjamin, E. J., Go, A. S., et al. (2015). Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation, 131(4), e29–322.
Qian, L., Huang, Y., Spencer, C. I., et al. (2012). In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature, 485(7400), 593–8.
Inagawa, K., Miyamoto, K., Yamakawa, H., et al. (2012). Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5. Circulation Research, 111(9), 1147–56.
Song, K., Nam, Y. J., Luo, X., et al. (2012). Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature, 485(7400), 599–604.
Jayawardena, T. M., Egemnazarov, B., Finch, E. A., et al. (2012). MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circulation Research, 110(11), 1465–73.
Jayawardena, T. M., Finch, E. A., Zhang, L., et al. (2015). MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function. Circulation Research, 116(3), 418–24.
Munshi, N. V., & Olson, E. N. (2014). Translational medicine. Improving cardiac rhythm with a biological pacemaker. Science, 345(6194), 268–9.
Kapoor, N., Liang, W., Marban, E., & Cho, H. C. (2013). Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nature Biotechnology, 31(1), 54–62.
Hu, Y. F., Dawkins, J. F., Cho, H. C., Marban, E., & Cingolani, E. (2014). Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Science Translational Medicine, 6(245), 245ra94.
Torper, O., Pfisterer, U., Wolf, D. A., et al. (2013). Generation of induced neurons via direct conversion in vivo. Proceedings of the National Academy of Sciences of the United States of America, 110(17), 7038–43.
Niu, W., Zang, T., Zou, Y., et al. (2013). In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nature Cell Biology, 15(10), 1164–75.
Niu, W., T. Zang, D.K. Smith, et al. (2015). SOX2 Reprograms resident astrocytes into neural progenitors in the adult brain. Stem Cell Reports.
Su, Z., Niu, W., Liu, M. L., Zou, Y., & Zhang, C. L. (2014). In vivo conversion of astrocytes to neurons in the injured adult spinal cord. Nature Communications, 5, 3338.
Yiu, G., & He, Z. (2006). Glial inhibition of CNS axon regeneration. Nature Review Neuroscience, 7(8), 617–27.
Guo, Z., Zhang, L., Wu, Z., Chen, Y., Wang, F., & Chen, G. (2014). In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell, 14(2), 188–202.
Rouaux, C., & Arlotta, P. (2013). Direct lineage reprogramming of post-mitotic callosal neurons into corticofugal neurons in vivo. Nature Cell Biology, 15(2), 214–21.
De la Rossa, A., Bellone, C., Golding, B., et al. (2013). In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons. Nature Neuroscience, 16(2), 193–200.
Vivien, C., Scerbo, P., Girardot, F., Le Blay, K., Demeneix, B. A., & Coen, L. (2012). Non-viral expression of mouse Oct4, Sox2, and Klf4 transcription factors efficiently reprograms tadpole muscle fibers in vivo. Journal of Biological Chemistry, 287(10), 7427–35.
Yilmazer, A., de Lazaro, I., Bussy, C., & Kostarelos, K. (2013). In vivo cell reprogramming towards pluripotency by virus-free overexpression of defined factors. PLoS One, 8(1), e54754.
Yilmazer, A., I. de Lazaro, C. Bussy, and K. Kostarelos. (2013). In vivo reprogramming of adult somatic cells to pluripotency by overexpression of Yamanaka factors. JoVE 17(82).
Acknowledgments
Irene de Lázaro would like to thank Obra Social LaCaixa, University College London (UCL) and the University of Manchester for jointly funding this project.
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de Lázaro, I., Kostarelos, K. Engineering Cell Fate for Tissue Regeneration by In Vivo Transdifferentiation. Stem Cell Rev and Rep 12, 129–139 (2016). https://doi.org/10.1007/s12015-015-9624-6
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DOI: https://doi.org/10.1007/s12015-015-9624-6