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Enhanced Functions of Human Embryonic Stem Cell-derived Hepatocyte-like Cells on Three-dimensional Nanofibrillar Surfaces

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An Author Correction to this article was published on 18 June 2021

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Abstract

Human embryonic stem cell (hESC)-derived hepatocytes provide a promising unlimited resource for the treatment of liver disease. However, current protocols for the generation of mature and functional hepatocytes are inefficient. Therefore, in order to better differentiate and maintain the function of differentiating hESCs, we have hypothesized that hESCs undergo better differentiation into hepatocyte-like cells (HLCs) when induced on three-dimensional nanofibrillar surfaces. We have demonstrated that, during stepwise differentiation of induction, the markers of hepatic lineage expressed and finally lead to the generation of functional mature cells. In the presence of an ultraweb nanofiber, HLCs produced lower AFP, greater urea, glycogen storage, metabolic PROD activity, uptake of LDL and organic anion ICG, all of which are indicative of the differentiation of HLCs. These results show that topographically treated hESCs at the nano level have a distinct hepatic functionality profile which has implications for cell therapies.

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References

  1. Haridass, D., Narain, N., & Ott, M. (2008). Hepatocyte transplantation: waiting for stem cells. Current Opinion in Organ Transplantation, 13, 627–632.

    Article  PubMed  Google Scholar 

  2. Basma, H., Soto-Gutierrez, A., Yannam, G. R., et al. (2009). Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology, 136, 990–999.

    Article  CAS  PubMed  Google Scholar 

  3. Hay, D. C., Zhao, D., Ross, A., Mandalam, R., Lebkowski, J., & Cui, W. (2007). Direct differentiation of human embryonic stem cells to hepatocyte-like cells exhibiting functional activities. Cloning and Stem Cells, 9, 51–62.

    Article  CAS  PubMed  Google Scholar 

  4. Duan, Y., Catana, A., Meng, Y., et al. (2007). Differentiation and enrichment of hepatocyte-like cells from human embryonic stem cells in vitro and in vivo. Stem Cells, 25, 3058–3068.

    Article  CAS  PubMed  Google Scholar 

  5. Baharvand, H., Hashemi, S. M., & Shahsavani, M. (2008). Differentiation of human embryonic stem cells into functional hepatocyte-like cells in a serum-free adherent culture condition. Differentiation, 76, 465–477.

    Article  CAS  PubMed  Google Scholar 

  6. Baharvand, H., Hashemi, S. M., Kazemi Ashtiani, S., & Farrokhi, A. (2006). Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. The International Journal of Developmental Biology, 50, 645–652.

    Article  CAS  PubMed  Google Scholar 

  7. Schwartz, R. E., Linehan, J. L., Painschab, M. S., Hu, W. S., Verfaillie, C. M., & Kaufman, D. S. (2005). Defined conditions for development of functional hepatic cells from human embryonic stem cells. Stem Cells and Development, 14, 643–655.

    Article  CAS  PubMed  Google Scholar 

  8. Lavon, N., Yanuka, O., & Benvenisty, N. (2004). Differentiation and isolation of hepatic-like cells from human embryonic stem cells. Differentiation, 72, 230–238.

    Article  CAS  PubMed  Google Scholar 

  9. Discher, D. E., Mooney, D. J., & Zandstra, P. W. (2009). Growth factors, matrices, and forces combine and control stem cells. Science, 324, 1673–1677.

    Article  CAS  PubMed  Google Scholar 

  10. Gerecht, S., Bettinger, C. J., Zhang, Z., Borenstein, J. T., Vunjak-Novakovic, G., & Langer, R. (2007). The effect of actin disrupting agents on contact guidance of human embryonic stem cells. Biomaterials, 28, 4068–4077.

    Article  CAS  PubMed  Google Scholar 

  11. Baharvand, H., & Mehrjardi, N., Z. (2008). Nanotechnology in stem cell biology and technology. In: Reisner, D. E., & Bronzino, J. D., (eds.), Bionanotechnology: Global Prospects Taylor & Francis, Inc.: 1–23.

  12. Dalby, M. J., Gadegaard, N., Tare, R., et al. (2007). The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder. Nature Materials, 6, 997–1003.

    Article  CAS  PubMed  Google Scholar 

  13. Brophy, C. M., Luebke-Wheeler, J. L., Amiot, B. P., Remmel, R. P., Rinaldo, P., & Nyberg, S. L. (2009/2010). Gene expression and functional analyses of primary rat hepatocytes on nanofiber matrices. Cells, Tissues, Organs, 191(2), 129–140.

    Article  Google Scholar 

  14. Schindler, M., Ahmed, I., Kamal, J., et al. (2005). A synthetic nanofibrillar matrix promotes in vivo-like organization and morphogenesis for cells in culture. Biomaterials, 26, 5624–5631.

    Article  CAS  PubMed  Google Scholar 

  15. Navarro-Alvarez, N., Soto-Gutierrez, A., & Kobayashi, N. (2009). Stem cell research and therapy for liver disease. Current Stem Cell Research & Therapy, 4, 141–146.

    Article  CAS  Google Scholar 

  16. Chai, C., & Leong, K. W. (2007). Biomaterials approach to expand and direct differentiation of stem cells. Molecular Therapy, 15, 467–480.

    Article  CAS  PubMed  Google Scholar 

  17. Cai, J., Zhao, Y., Liu, Y., et al. (2007). Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology, 45, 1229–1239.

    Article  CAS  PubMed  Google Scholar 

  18. Agarwal, S., Holton, K. L., & Lanza, R. (2008). Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells, 26, 1117–1127.

    Article  CAS  PubMed  Google Scholar 

  19. Tzanakakis, E. S., Hsiao, C. C., Matsushita, T., Remmel, R. P., & Hu, W. S. (2001). Probing enhanced cytochrome P450 2B1/2 activity in rat hepatocyte spheroids through confocal laser scanning microscopy. Cell Transplantation, 10, 329–342.

    CAS  PubMed  Google Scholar 

  20. McGrath, K. E., Koniski, A. D., Maltby, K. M., McGann, J. K., & Palis, J. (1999). Embryonic expression and function of the chemokine SDF-1 and its receptor, CXCR4. Developmental Biology, 213, 442–456.

    Article  CAS  PubMed  Google Scholar 

  21. Yasunaga, M., Tada, S., Torikai-Nishikawa, S., et al. (2005). Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nature Biotechnology, 23, 1542–1550.

    Article  CAS  PubMed  Google Scholar 

  22. Piryaei, A., Valojerdi, M. R., Shahsavani, M., & Baharvand, H. (2010). Differentiation of bone marrow-derived mesenchymal stem cells into hepatocyte-like cells on nanofibers and their transplantation into a carbon tetrachloride-induced liver fibrosis model Stem Cell Rev. In press.

  23. Hashemi, S. M., Soleimani, M., Zargarian, S. S., et al. (2009). In vitro differentiation of human cord blood-derived unrestricted somatic stem cells into hepatocyte-like cells on poly(epsilon-caprolactone) nanofiber scaffolds. Cells, Tissues, Organs, 190, 135–149.

    Article  CAS  PubMed  Google Scholar 

  24. Hosseinkhani, H., Hosseinkhani, M., Tian, F., Kobayashi, H., & Tabata, Y. (2006). Osteogenic differentiation of mesenchymal stem cells in self-assembled peptide-amphiphile nanofibers. Biomaterials, 27, 4079–4086.

    Article  CAS  PubMed  Google Scholar 

  25. Woo, K. M., Jun, J. H., Chen, V. J., et al. (2007). Nano-fibrous scaffolding promotes osteoblast differentiation and biomineralization. Biomaterials, 28, 335–343.

    Article  CAS  PubMed  Google Scholar 

  26. Elias, K. L., Price, R. L., & Webster, T. J. (2002). Enhanced functions of osteoblasts on nanometer diameter carbon fibers. Biomaterials, 23, 3279–3287.

    Article  CAS  PubMed  Google Scholar 

  27. Li, W. J., Tuli, R., Okafor, C., et al. (2005). A three-dimensional nanofibrous scaffold for cartilage tissue engineering using human mesenchymal stem cells. Biomaterials, 26, 599–609.

    Article  CAS  PubMed  Google Scholar 

  28. Silva, G. A., Czeisler, C., Niece, K. L., et al. (2004). Selective differentiation of neural progenitor cells by high-epitope density nanofibers. Science, 303, 1352–1355.

    Article  CAS  PubMed  Google Scholar 

  29. Lovat, V., Pantarotto, D., Lagostena, L., et al. (2005). Carbon nanotube substrates boost neuronal electrical signaling. Nano Letters, 5, 1107–1110.

    Article  CAS  PubMed  Google Scholar 

  30. Nur, E. K. A., Ahmed, I., Kamal, J., Schindler, M., & Meiners, S. (2006). Three-dimensional nanofibrillar surfaces promote self-renewal in mouse embryonic stem cells. Stem Cells, 24, 426–433.

    Article  Google Scholar 

  31. Blin, G., Lablack, N., Louis-Tisserand, M., Nicolas, C., Picart, C., & Puceat, M. Nano-scale control of cellular environment to drive embryonic stem cells selfrenewal and fate. Biomaterials, 31, 1742-1750.

  32. Christopherson, G. T., Song, H., & Mao, H. Q. (2009). The influence of fiber diameter of electrospun substrates on neural stem cell differentiation and proliferation. Biomaterials, 30, 556–564.

    Article  CAS  PubMed  Google Scholar 

  33. Guilak, F., Cohen, D. M., Estes, B. T., Gimble, J. M., Liedtke, W., & Chen, C. S. (2009). Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell, 5, 17–26.

    Article  CAS  PubMed  Google Scholar 

  34. Arnold, M., Cavalcanti-Adam, E. A., Glass, R., et al. (2004). Activation of integrin function by nanopatterned adhesive interfaces. Chemphyschem, 5, 383–388.

    Article  CAS  PubMed  Google Scholar 

  35. Martínez, E., Lagunas, A., Mills, C., et al. (2009). Stem cell differentiation by functionalized micro- and nanostructured surfaces. Nanomedicine, 4, 65–82.

    Article  PubMed  Google Scholar 

  36. Nur, E. K. A., Ahmed, I., Kamal, J., Schindler, M., & Meiners, S. (2005). Three dimensional nanofibrillar surfaces induce activation of Rac. Biochemical and Biophysical Research Communications, 331, 428–434.

    Article  Google Scholar 

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Acknowledgments

We gratefully acknowledge Mehdi Pirouz, Mohammad Pakzad, and Abbas Piryaei for their critical comments and technical support. This study was funded by a grant from Royan Institute.

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Correspondence to Hossein Baharvand.

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Table 1

Primer sequences and condition of PCR (DOC 43 kb)

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Farzaneh, Z., Pournasr, B., Ebrahimi, M. et al. Enhanced Functions of Human Embryonic Stem Cell-derived Hepatocyte-like Cells on Three-dimensional Nanofibrillar Surfaces. Stem Cell Rev and Rep 6, 601–610 (2010). https://doi.org/10.1007/s12015-010-9179-5

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