Int J Stem Cells.  2014 Nov;7(2):49-54. 10.15283/ijsc.2014.7.2.49.

Concise Review: Differentiation of Human Adult Stem Cells Into Hepatocyte-like Cells In vitro

• Zhang Y
• Xu L
• Wang S
• Cai C
• Yan L

• KMID: 1974591
• DOI: http://doi.org/10.15283/ijsc.2014.7.2.49

Abstract

Adult stem cells (ASCs) are undifferentiated cells found throughout the body that divide to replenish dying cells and regenerate damaged tissues, which are the powerful sources for cell therapy and tissue engineering. Bone marrow-derived mesenchymal stem cells (BMSCs), adipose tissue-derived mesenchymal stem cells (ADSCs), and peripheral blood monocytes (PBMCs) are the common ASCs, and many studies indicated that ASCs isolated from various adult tissues could be induced to hepatocyte-like cells in vitro. However, the isolation, culture protocols, characterization of ASCs and hepatocyte-like cells are different. This review aims to describe the isolation and culture procedures for ASCs, to summarize the molecular characterization of ASCs, to characterize function of hepatocyte-like cells, and to discuss the future role of ASCs in cell therapy and tissue engineering.

Keyword

Adult stem cells; Bone marrow-derived mesenchymal stem cells; Adipose tissue-derived mesenchymal stem cells Peripheral blood monocytes; Hepatocyte-like cells

MeSH Terms

Adult
Adult Stem Cells*
Cell- and Tissue-Based Therapy
Humans
Mesenchymal Stromal Cells
Monocytes
Tissue Engineering

Reference

References

1. Dhawan A, Puppi J, Hughes RD, Mitry RR. Human hepatocyte transplantation: current experience and future challenges. Nat Rev Gastroenterol Hepatol. 2010. 7:288–298.

2. Navarro-Alvarez N, Soto-Gutierrez A, Kobayashi N. Hepatocyte transplantation: a step forward. Curr Opin Organ Transplant. 2007. 12:652–658.

3. Zaret KS, Grompe M. Generation and regeneration of cells of the liver and pancreas. Science. 2008. 322:1490–1494.

4. Terry C, Hughes RD, Mitry RR, Lehec SC, Dhawan A. Cryopreservation-induced nonattachment of human hepatocytes: role of adhesion molecules. Cell Transplant. 2007. 16:639–647.

5. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998. 282:1145–1147.

6. Gallicano GI, Mishra L. Hepatocytes from induced pluripotent stem cells: a giant leap forward for hepatology. Hepatology. 2010. 51:20–22.

7. Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, Chen JR, Chen YP, Lee OK. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology. 2004. 40:1275–1284.

8. Snykers S, Vanhaecke T, Papeleu P, Luttun A, Jiang Y, Vander Heyden Y, Verfaillie C, Rogiers V. Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into functional hepatocyte-like cells. Toxicol Sci. 2006. 94:330–341.

9. Lee MJ, Jung J, Na KH, Moon JS, Lee HJ, Kim JH, Kim GI, Kwon SW, Hwang SG, Kim GJ. Anti-fibrotic effect of chorionic plate-derived mesenchymal stem cells isolated from human placenta in a rat model of CCl(4)-injured liver: potential application to the treatment of hepatic diseases. J Cell Biochem. 2010. 111:1453–1463.

10. Shin KS, Lee HJ, Jung J, Cha DH, Kim GJ. Culture and in vitro hepatogenic differentiation of placenta-derived stem cells, using placental extract as an alternative to serum. Cell Prolif. 2010. 43:435–444.

11. Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000. 6:1229–1234.

12. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002. 418:41–49.

13. Jang YY, Collector MI, Baylin SB, Diehl AM, Sharkis SJ. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol. 2004. 6:532–539.

14. di Bonzo LV, Ferrero I, Cravanzola C, Mareschi K, Rustichell D, Novo E, Sanavio F, Cannito S, Zamara E, Bertero M, Davit A, Francica S, Novelli F, Colombatto S, Fagioli F, Parola M. Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential. Gut. 2008. 57:223–231.

15. Chen Y, Dong XJ, Zhang GR, Shao JZ, Xiang LX. In vitro differentiation of mouse bone marrow stromal stem cells into hepatocytes induced by conditioned culture medium of hepatocytes. J Cell Biochem. 2007. 102:52–63.

16. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001. 7:211–228.

17. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002. 13:4279–4295.

18. Matsunaga T, Sakamaki S, Kohgo Y, Ohi S, Hirayama Y, Niitsu Y. Recombinant human granulocyte colony-stimulating factor can mobilize sufficient amounts of peripheral blood stem cells in healthy volunteers for allogeneic transplantation. Bone Marrow Transplant. 1993. 11:103–108.

19. Kasai M, Kiyama Y, Kawamura A. Application of peripheral blood stem cells (PBSC) mobilized by recombinant human granulocyte colony stimulating factor for allogeneic PBSC transplantation and the comparison of allogeneic PBSC transplantation and bone marrow transplantation. Transfus Apher Sci. 2002. 26:121–127.

20. Conget PA, Minguell JJ. Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. J Cell Physiol. 1999. 181:67–73.

21. De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M, Dragoo JL, Ashjian P, Thomas B, Benhaim P, Chen I, Fraser J, Hedrick MH. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs. 2003. 174:101–109.

22. Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U, Blake J, Schwager C, Eckstein V, Ansorge W, Ho AD. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol. 2005. 33:1402–1416.

23. Lee RH, Kim B, Choi I, Kim H, Choi HS, Suh K, Bae YC, Jung JS. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem. 2004. 14:311–324.

24. Katz AJ, Tholpady A, Tholpady SS, Shang H, Ogle RC. Cell surface and transcriptional characterization of human adipose-derived adherent stromal (hADAS) cells. Stem Cells. 2005. 23:412–423.

25. Gronthos S, Franklin DM, Leddy HA, Robey PG, Storms RW, Gimble JM. Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol. 2001. 189:54–63.

26. Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006. 24:1294–1301.

27. Strem BM, Hicok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE, Fraser JK, Hedrick MH. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med. 2005. 54:132–141.

28. Dicker A, Le Blanc K, Aström G, van Harmelen V, Götherström C, Blomqvist L, Arner P, Rydén M. Functional studies of mesenchymal stem cells derived from adult human adipose tissue. Exp Cell Res. 2005. 308:283–290.

29. Im GI, Shin YW, Lee KB. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthritis Cartilage. 2005. 13:845–853.

30. Safford KM, Hicok KC, Safford SD, Halvorsen YD, Wilkison WO, Gimble JM, Rice HE. Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochem Biophys Res Commun. 2002. 294:371–379.

31. Cao Y, Sun Z, Liao L, Meng Y, Han Q, Zhao RC. Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun. 2005. 332:370–379.

32. Seo MJ, Suh SY, Bae YC, Jung JS. Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem Biophys Res Commun. 2005. 328:258–264.

33. Boquest AC, Shahdadfar A, Frønsdal K, Sigurjonsson O, Tunheim SH, Collas P, Brinchmann JE. Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture. Mol Biol Cell. 2005. 16:1131–1141.

34. Sgodda M, Aurich H, Kleist S, Aurich I, König S, Dollinger MM, Fleig WE, Christ B. Hepatocyte differentiation of mesenchymal stem cells from rat peritoneal adipose tissue in vitro and in vivo. Exp Cell Res. 2007. 313:2875–2886.

35. Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, Lenvik T, Johnson S, Hu WS, Verfaillie CM. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest. 2002. 109:1291–1302.

36. Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, Chen JR, Chen YP, Lee OK. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology. 2004. 40:1275–1284.

37. Anjos-Afonso F, Siapati EK, Bonnet D. In vivo contribution of murine mesenchymal stem cells into multiple cell-types under minimal damage conditions. J Cell Sci. 2004. 117:5655–5664.

38. Aurich I, Mueller LP, Aurich H, Luetzkendorf J, Tisljar K, Dollinger MM, Schormann W, Walldorf J, Hengstler JG, Fleig WE, Christ B. Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers. Gut. 2007. 56:405–415.

39. Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006. 24:1294–1301.

40. Lee RH, Kim B, Choi I, Kim H, Choi HS, Suh K, Bae YC, Jung JS. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem. 2004. 14:311–324.

41. Seo MJ, Suh SY, Bae YC, Jung JS. Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem Biophys Res Commun. 2005. 328:258–264.

42. Fiegel HC, Lioznov MV, Cortes-Dericks L, Lange C, Kluth D, Fehse B, Zander AR. Liver-specific gene expression in cultured human hematopoietic stem cells. Stem Cells. 2003. 21:98–104.

43. Takeda M, Yamamoto M, Isoda K, Higashiyama S, Hirose M, Ohgushi H, Kawase M, Yagi K. Availability of bone marrow stromal cells in three-dimensional coculture with hepatocytes and transplantation into liver-damaged mice. J Biosci Bioeng. 2005. 100:77–81.

44. Snykers S, Vanhaecke T, Papeleu P, Luttun A, Jiang Y, Vander Heyden Y, Verfaillie C, Rogiers V. Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into functional hepatocyte-like cells. Toxicol Sci. 2006. 94:330–341.

45. Seo MJ, Suh SY, Bae YC, Jung JS. Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem Biophys Res Commun. 2005. 328:258–264.

46. Taléns-Visconti R, Bonora A, Jover R, Mirabet V, Carbonell F, Castell JV, Gómez-Lechón MJ. Hepatogenic differentiation of human mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells. World J Gastroenterol. 2006. 12:5834–5845.

47. Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Quinn G, Okochi H, Ochiya T. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology. 2007. 46:219–228.

48. Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Osaki M, Kato T, Okochi H, Ochiya T. Rapid hepatic fate specification of adipose-derived stem cells and their therapeutic potential for liver failure. J Gastroenterol Hepatol. 2009. 24:70–77.

49. Aurich H, Sgodda M, Kaltwasser P, Vetter M, Weise A, Liehr T, Brulport M, Hengstler JG, Dollinger MM, Fleig WE, Christ B. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut. 2009. 58:570–581.

50. Okura H, Komoda H, Saga A, Kakuta-Yamamoto A, Hamada Y, Fumimoto Y, Lee CM, Ichinose A, Sawa Y, Matsuyama A. Properties of hepatocyte-like cell clusters from human adipose tissue-derived mesenchymal stem cells. Tissue Eng Part C Methods. 2010. 16:761–770.

51. Ruhnke M, Ungefroren H, Nussler A, Martin F, Brulport M, Schormann W, Hengstler JG, Klapper W, Ulrichs K, Hutchinson JA, Soria B, Parwaresch RM, Heeckt P, Kremer B, Fändrich F. Differentiation of in vitro-modified human peripheral blood monocytes into hepatocyte-like and pancreatic islet-like cells. Gastroenterology. 2005. 128:1774–1786.