Advertisement

Journal of Zhejiang University SCIENCE B

, Volume 14, Issue 11, pp 961–972 | Cite as

Menstrual blood-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells

  • Xiao-zhou Mou
  • Jian Lin
  • Jin-yang Chen
  • Yi-fei Li
  • Xiao-xing Wu
  • Bing-yu Xiang
  • Cai-yun Li
  • Ju-ming Ma
  • Charlie Xiang
Article

Abstract

Orthotopic liver transplantation (OLT) is the only proven effective treatment for both end-stage and metabolic liver diseases. Hepatocyte transplantation is a promising alternative for OLT, but the lack of available donor livers has hampered its clinical application. Hepatocyte-like cells (HLCs) differentiated from many multi-potential stem cells can help repair damaged liver tissue. Yet almost suitable cells currently identified for human use are difficult to harvest and involve invasive procedures. Recently, a novel mesenchymal stem cell derived from human menstrual blood (MenSC) has been discovered and obtained easily and repeatedly. In this study, we examined whether the MenSCs are able to differentiate into functional HLCs in vitro. After three weeks of incubation in hepatogenic differentiation medium containing hepatocyte growth factor (HGF), fibroblast growth factor-4 (FGF-4), and oncostain M (OSM), cuboidal HLCs were observed, and cells also expressed hepatocyte-specific marker genes including albumin (ALB), α-fetoprotein (AFP), cytokeratin 18/19 (CK18/19), and cytochrome P450 1A1/3A4 (CYP1A1/3A4). Differentiated cells further demonstrated in vitro mature hepatocyte functions such as urea synthesis, glycogen storage, and indocyanine green (ICG) uptake. After intrasplenic transplantation into mice with 2/3 partial hepatectomy, the MenSC-derived HLCs were detected in recipient livers and expressed human ALB protein. We also showed that MenSC-derived HLC transplantation could restore the serum ALB level and significantly suppressed transaminase activity of liver injury animals. In conclusion, MenSCs may serve as an ideal, easily accessible source of material for tissue engineering and cell therapy of liver tissues.

Key words

Menstrual blood-derived mesenchymal stem cell (MenSC) Differentiation Hepatocyte Intrasplenic transplantation Partial hepatectomy 

CLC number

Q813 R51 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Allickson, J., Xiang, C., 2012. Human adult stem cells from menstrual blood and endometrial tissue. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 13(5):419–420. [doi:10.1631/jzus.B1200062]CrossRefGoogle Scholar
  2. Allickson, J.G., Sanchez, A., Yefimenko, N., Borlongan, C.V., Sanberg, P.R., 2011. Recent studies assessing the proliferative capability of a novel adult stem cell identified in menstrual blood. Open Stem Cell J., 3(2011):4–10. [doi:10.2174/1876893801103010004]PubMedCrossRefGoogle Scholar
  3. Banas, A., Teratani, T., Yamamoto, Y., Tokuhara, M., Takeshita, F., Quinn, G., Okochi H., Ochiya, T., 2007. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology, 46(1):219–228. [doi:10.1002/hep.21704]PubMedCrossRefGoogle Scholar
  4. Bieback, K., Kern, S., Kluter, H., Eichler, H., 2004. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells, 22(4):625–634. [doi:10.1634/stemcells.22-4-625]PubMedCrossRefGoogle Scholar
  5. Borlongan, C., Kaneko, V.Y., Maki, M., Yu, S.J., Ali, M., Allickson, J.G., Sanberg, C.D., Kuzmin-Nichols, N., Sanberg, P.R., 2010. Menstrual blood cells display stem cell-like phenotypic markers and exert neuroprotection following transplantation in experimental stroke. Stem Cells Dev., 19(4):439–452. [doi:10.1089/scd.2009.0340]PubMedCrossRefGoogle Scholar
  6. Chen, Y., Dong, X.J., Zhang, G.R., Shao J.Z., Xiang, L.X., 2007. In vitro differentiation of mouse bone marrow stromal stem cells into hepatocytes induced by conditioned culture medium of hepatocytes. J. Cell Biochem., 102(1):52–63. [doi:10.1002/jcb.21275]PubMedCrossRefGoogle Scholar
  7. Chen, Y.F., Tseng, C.Y., Wang, H.W., Kuo, H.C., Yang, V.W., Lee, O.K., 2012. Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol. Hepatology, 55(4): 1193–1203. [doi:10.1002/hep.24790]PubMedCrossRefGoogle Scholar
  8. Chien, C.C., Yen, B.L., Lee, F.K., Lai, T.H., Chen, Y.C., Chan, S.H., Huang, H.I., 2006. In vitro differentiation of human placenta-derived multipotent cells into hepatocyte-like cells. Stem Cells, 24(7):1759–1768. [doi:10.1634/stem cells.2005-0521]PubMedCrossRefGoogle Scholar
  9. Cui, C.H., Uyama, T., Miyado, K., Terai, M., Kyo, S., Kiyono, T., Umezawa, A., 2007. Menstrual blood-derived cells confer human dystrophin expression in the murine model of Duchenne muscular dystrophy via cell fusion and myogenic transdifferentiation. Mol. Biol. Cell, 18(5): 1586–1594. [doi:10.1091/mbc.E06-09-0872]PubMedCrossRefGoogle Scholar
  10. de Coppi, P., Bartsch, G.Jr., Siddiqui, M.M., Xu, T., Santos, C.C., Perin, L., Mostoslavsky, G., Serre, A.C., Snyder, E.Y., Yoo, J.J., et al., 2007. Isolation of amniotic stem cell lines with potential for therapy. Nat. Biotechnol., 25(1):100–106. [doi:10.1038/nbt1274]PubMedCrossRefGoogle Scholar
  11. Dhawan, A., Mitry, R.R., Hughes, R.D., Lehec, S., Terry, C., Bansal, S., Arya, R., Wade, J.J., Verma, A., Heaton, N.D., et al., 2004. Hepatocyte transplantation for inherited factor VII deficiency. Transplantation, 78(12):1812–1814. [doi:10.1097/01.TP.0000146386.77076.47]PubMedCrossRefGoogle Scholar
  12. Fox, I.J., Chowdhury, J.R., 2004. Hepatocyte transplantation. J. Hepatol., 40(6):878–886. [doi:10.1016/j.jhep.2004.04.009]PubMedCrossRefGoogle Scholar
  13. Fox, I.J., Chowdhury, J.R., Kaufman, S.S., Goertzen, T.C., Chowdhury, N.R., Warkentin, P.I., Dorko, K., Sauter, B.V., Strom, S.C., 1998. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N. Engl. J. Med., 338(20):1422–1426. [doi:10.1056/NEJM199805 143382004]PubMedCrossRefGoogle Scholar
  14. Gunsalus, J.R., Brady, D.A., Coulter, S.M., Gray, B.M., Edge, A.S., 1997. Reduction of serum cholesterol in Watanabe rabbits by xenogeneic hepatocellular transplantation. Nat. Med., 3(1):48–53. [doi:10.1038/nm0197-48]PubMedCrossRefGoogle Scholar
  15. Hida, N., Nishiyama, N., Miyoshi, S., Kira, S., Segawa, K., Uyama, T., Mori, T., Miyado, K., Ikegami, Y., Cui, C., et al., 2008. Novel cardiac precursor-like cells from human menstrual blood-derived mesenchymal cells. Stem Cells, 26(7):1695–1704. [doi:10.1634/stemcells.2007-0826]PubMedCrossRefGoogle Scholar
  16. Huang, P., He, Z., Ji, S., Sun, H., Xiang, D., Liu, C., Hu, Y., Wang, X., Hui, L., 2011. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature, 475(7356):386–389. [doi:10.1038/nature 10116]PubMedCrossRefGoogle Scholar
  17. Ikegami, Y., Miyoshi, S., Nishiyama, N., Hida, N., Okamoto, K., Miyado, K., Segawa, K., Ogawa, S., Umezawa, A., 2010. Serum-independent cardiomyogenic transdifferentiation in human endometrium-derived mesenchymal cells. Artif. Organs, 34(4):280–288. [doi:10.1111/j.1525-1594.2009.00859.x]PubMedCrossRefGoogle Scholar
  18. Lee, K.D., Kuo, T.K., Whang-Peng, J., Chung, Y.F., Lin, C.T., Chou, S.H., Chen, J.R., Chen, Y.P., Lee, O.K., 2004. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology, 40(6):1275–1284. [doi:10.1002/hep. 20469]PubMedCrossRefGoogle Scholar
  19. Li, H.Y., Chen, Y.J., Chen, S.J., Kao, C.L., Tseng, L.M., Lo, W.L., Chang, C.M., Yang, D.M., Ku, H.H., Twu, N.F., et al., 2010. Induction of insulin-producing cells derived from endometrial mesenchymal stem-like cells. J. Pharmacol. Exp. Ther., 335(3):817–829. [doi:10.1124/jpet.110.169284]PubMedCrossRefGoogle Scholar
  20. Li, J., Tao, R., Wu, W., Cao, H., Xin, J., Guo, J., Jiang, L., Hong, X., Demetriou, A.A., Farkas, D., et al., 2010. Transcriptional profiling and hepatogenic potential of acute hepatic failure-derived bone marrow mesenchymal stem cells. Differentiation, 80(2–3):166–174. [doi:10.1016/j.diff.2010.04.002]PubMedCrossRefGoogle Scholar
  21. Lin, J., Xiang, D., Zhang, J.L., Allickson, J., Xiang, C., 2011. Plasticity of human menstrual blood stem cells derived from the endometrium. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 12(5):372–380. [doi:10.1631/jzus. B1100015]CrossRefGoogle Scholar
  22. Meng, X., Ichim, T.E., Zhong, J., Rogers, A., Yin, Z., Jackson, J., Wang, H., Ge, W., Bogin, V., Chan, K.W., et al., 2007. Endometrial regenerative cells: a novel stem cell population. J. Transl. Med., 5:57. [doi:10.1186/1479-5876-5-57]PubMedCrossRefGoogle Scholar
  23. Mitchell, C., Willenbring, H., 2008. A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice. Nat. Protoc., 3(7):1167–1170. [doi:10.1038/nprot.2008.80]PubMedCrossRefGoogle Scholar
  24. Muraca, M., Gerunda, G., Neri, D., Vilei, M.T., Granato, A., Feltracco, P., Meroni, M., Giron, G., Burlina, A.B., 2002. Hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet, 359(9303):317–318. [doi:10.1016/S0140-6736(02)07529-3]PubMedCrossRefGoogle Scholar
  25. Murphy, M.P., Wang, H., Patel, A.N., Kambhampati, S., Angle, N., Chan, K., Marleau, A.M., Pyszniak, A., Carrier, E., Ichim, T.E., et al., 2008. Allogeneic endometrial regenerative cells: an “off the shelf solution” for critical limb ischemia? J. Transl. Med., 6(1):45. [doi:10.1186/1479-5876-6-45]PubMedCrossRefGoogle Scholar
  26. Overturf, K., Al-Dhalimy, M., Tanguay, R., Brantly, M., Ou, C.N., Finegold, M., Grompe, M., 1996. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat. Genet., 12(3):266–273. [doi:10.1038/ng0396-266]PubMedCrossRefGoogle Scholar
  27. Park, S.M., Vo, K., Lallier, M., Cloutier, A.S., Brochu, P., Alvarez, F., Martin, S.R., 2006. Hepatocyte transplantation in the Long Evans Cinnamon rat model of Wilson’s disease. Cell Transplant., 15(1):13–22. [doi:10.3727/000000006783982188]PubMedCrossRefGoogle Scholar
  28. Patel, A.N., Silva, F., 2008. Menstrual blood stromal cells: the potential for regenerative medicine. Regen. Med., 3(4): 443–444. [doi:10.2217/17460751.3.4.443]PubMedCrossRefGoogle Scholar
  29. Patel, A.N., Park, E., Kuzman, M., Benetti, F., Silva, F.J., Allickson, J.G., 2008. Multipotent menstrual blood stromal stem cells: isolation, characterization, and differentiation. Cell Transplant., 17(3):303–311. [doi:10.3727/096368908784153922]PubMedCrossRefGoogle Scholar
  30. Peleman, R.R., Gavaler, J.S., van Thiel, D.H., Esquivel, C., Gordon, R., Iwatsuki, S., Starzl, T.E., 1987. Orthotopic liver transplantation for acute and subacute hepatic failure in adults. Hepatology, 7(3):484–489. [doi:10.1002/hep. 1840070312]PubMedCrossRefGoogle Scholar
  31. Phuc, P.V., Lam, D.H., Ngoc, V.B., Thu, D.T., Nguyet, N.T., Ngoc, P.K., 2011. Production of functional dendritic cells from menstrual blood—a new dendritic cell source for immune therapy. In Vitro Cell Dev. Biol. Anim., 47(5–6): 368–375. [doi:10.1007/s11626-011-9399-2]PubMedCrossRefGoogle Scholar
  32. Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Moorman, M.A., Simonetti, D.W., Craig, S., Marshak, D.R., 1999. Multilineage potential of adult human mesenchymal stem cells. Science, 284(5411):143–147. [doi:10.1126/science.284.5411.143]PubMedCrossRefGoogle Scholar
  33. Sanberg, P.R., Eve, D.J., Willing, A.E., Garbuzova-Davis, S., Tan, J., Sanberg, C.D., Allickson, J.G., Cruz, L.E., Borlongan, C.V., 2011. The treatment of neurodegenerative disorders using umbilical cord blood and menstrual blood-derived stem cells. Cell Transplant., 20(1):85–94. [doi:10.3727/096368910X532855]PubMedCrossRefGoogle Scholar
  34. Santamaria, X., Massasa, E.E., Feng, Y., Wolff, E., Taylor, H.S., 2011. Derivation of insulin producing cells from human endometrial stromal stem cells and use in the treatment of murine diabetes. Mol. Ther., 19(11): 2065–2071. [doi:10.1038/mt.2011.173]PubMedCrossRefGoogle Scholar
  35. Schwab, K.E., Gargett, C.E., 2007. Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Hum. Reprod., 22(11): 2903–2911. [doi:10.1093/humrep/dem265]PubMedCrossRefGoogle Scholar
  36. Schwartz, R.E., Reyes, M., Koodie, L., Jiang, Y., Blackstad, M., Lund, T., Lenvik, T., Johnson, S., Hu, W.S., Verfaillie, C.M., 2002. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J. Clin. Invest., 109(10):1291–1302. [doi:10.1172/JCI15182]PubMedGoogle Scholar
  37. Seo, M.J., Suh, S.Y., Bae, Y.C., Jung, J.S., 2005. Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem. Biophys. Res. Commun., 328(1):258–264. [doi:10.1016/j.bbrc.2004.12.158]PubMedCrossRefGoogle Scholar
  38. Snykers, S., Vanhaecke, T., Papeleu, P., Luttun, A., Jiang, Y., van der Heyden, Y., Verfaillie, C., Rogiers, V., 2006. 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., 94(2):330–341. [doi:10.1093/toxsci/kfl058]PubMedCrossRefGoogle Scholar
  39. Stephenne, X., Najimi, M., Sibille, C., Nassogne, M.C., Smets, F., Sokal, E.M., 2006. Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology, 130(4): 1317–1323. [doi:10.1053/j.gastro.2006.01.008]PubMedCrossRefGoogle Scholar
  40. Toyoda, M., Cui, C., Umezawa, A., 2007. Myogenic transdifferentiation of menstrual blood-derived cells. Acta Myol., 26(3):176–178.PubMedGoogle Scholar
  41. Yamamoto, H., Quinn, G., Asari, A., Yamanokuchi, H., Teratani, T., Terada, M., Ochiya, T., 2003. Differentiation of embryonic stem cells into hepatocytes: biological functions and therapeutic application. Hepatology, 37(5): 983–993. [doi:10.1053/jhep.2003.50202]PubMedCrossRefGoogle Scholar
  42. Yu, J., Yang, J., Pan, Q., Ma, J., Li, J., Li, Y., Cao, H., Wang, Y., Li, L., 2012. In vivo hepatic differentiation of mesenchymal stem cells from human umbilical cord blood after transplantation into mice with liver injury. Biochem. Biophys. Res. Commun., 422(4):539–545. [doi:10.1016/j.bbrc.2012.04.156]PubMedCrossRefGoogle Scholar

Copyright information

© Zhejiang University and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Xiao-zhou Mou
    • 1
    • 2
  • Jian Lin
    • 1
    • 3
  • Jin-yang Chen
    • 2
    • 4
  • Yi-fei Li
    • 1
  • Xiao-xing Wu
    • 1
  • Bing-yu Xiang
    • 1
  • Cai-yun Li
    • 5
  • Ju-ming Ma
    • 5
  • Charlie Xiang
    • 1
    • 2
    • 6
  1. 1.State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
  2. 2.Institute for Cell-Based Drug Development of Zhejiang ProvinceHangzhouChina
  3. 3.People’s Hospital of TonglingTonglingChina
  4. 4.S-Evans BiosciencesHangzhouChina
  5. 5.The 117th Hospital of PLAHangzhouChina
  6. 6.Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesHangzhouChina

Personalised recommendations