Stem Cell Reviews and Reports

, Volume 12, Issue 1, pp 129–139 | Cite as

Engineering Cell Fate for Tissue Regeneration by In Vivo Transdifferentiation

Article

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.

Key words

Transdifferentiation Reprogramming Cell fate Regeneration Tissue repair 

References

  1. 1.
    Graf, T. (2011). Historical origins of transdifferentiation and reprogramming. Cell Stem Cell, 9(6), 504–16.CrossRefPubMedGoogle Scholar
  2. 2.
    Slack, J. M. (2007). Metaplasia and transdifferentiation: from pure biology to the clinic. Nature Reviews Molecular Cell Biology, 8(5), 369–78.CrossRefPubMedGoogle Scholar
  3. 3.
    Davis, R. L., Weintraub, H., & Lassar, A. B. (1987). Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell, 51(6), 987–1000.CrossRefPubMedGoogle Scholar
  4. 4.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    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.CrossRefPubMedGoogle Scholar
  6. 6.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    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.CrossRefPubMedGoogle Scholar
  8. 8.
    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.CrossRefPubMedGoogle Scholar
  9. 9.
    Barrett, N. R. (1957). The lower esophagus lined by columnar epithelium. Surgery, 41(6), 881–94.PubMedGoogle Scholar
  10. 10.
    Spechler, S. J. (2002). Clinical practice. Barrett’s Esophagus. New England Journal of Medicine, 346(11), 836–42.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefPubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Li, Y., & Huard, J. (2002). Differentiation of muscle-derived cells into myofibroblasts in injured skeletal muscle. American Journal of Pathology, 161(3), 895–907.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhang, R., Han, P., Yang, H., et al. (2013). In vivo cardiac reprogramming contributes to zebrafish heart regeneration. Nature, 498(7455), 497–501.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Suetsugu-Maki, R., Maki, N., Nakamura, K., et al. (2012). Lens regeneration in axolotl: new evidence of developmental plasticity. BMC Biology, 10, 103.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 23.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151), 313–7.CrossRefPubMedGoogle Scholar
  26. 26.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedGoogle Scholar
  30. 30.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    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.CrossRefPubMedGoogle Scholar
  33. 33.
    Munshi, N. V., & Olson, E. N. (2014). Translational medicine. Improving cardiac rhythm with a biological pacemaker. Science, 345(6194), 268–9.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    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.CrossRefPubMedGoogle Scholar
  38. 38.
    Niu, W., T. Zang, D.K. Smith, et al. (2015). SOX2 Reprograms resident astrocytes into neural progenitors in the adult brain. Stem Cell Reports.Google Scholar
  39. 39.
    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.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Yiu, G., & He, Z. (2006). Glial inhibition of CNS axon regeneration. Nature Review Neuroscience, 7(8), 617–27.CrossRefGoogle Scholar
  41. 41.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    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.CrossRefPubMedGoogle Scholar
  44. 44.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    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).Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Nanomedicine Lab, Institute of Inflammation and Repair, Faculty of Medical and Human SciencesThe University of ManchesterManchesterUK
  2. 2.UCL School of Pharmacy, Faculty of Life SciencesUniversity College London (UCL)LondonUK

Personalised recommendations