Human Cell

, Volume 32, Issue 2, pp 125–140 | Cite as

Regulation of CCl4-induced liver cirrhosis by hepatically differentiated human dental pulp stem cells

  • Tomomi Yokoyama
  • Hiromi Yagi Mendoza
  • Tomoko Tanaka
  • Hisataka Ii
  • Riya Takano
  • Ken YaegakiEmail author
  • Hiroshi Ishikawa
Research Article


Liver transplantation is the most effective treatment for treating liver cirrhosis. However, a limited number of donors, graft rejection, and other complications can undermine transplant success. It is considered that cell transplantation is an alternative approach of liver transplantation. We previously developed a protocol for hepatic differentiation of cluster of differentiation 117+ stem cells isolated from human exfoliated deciduous tooth pulp (SHEDs) under hydrogen sulfide exposure. These cells showed excellent hepatic function. Here, we investigated whether hepatocyte-like cell transplantation is effective for treating carbon tetrachloride (CCl4)-induced liver cirrhosis. SHEDs were hepatically differentiated, which was confirmed via immunological analyses and albumin concentration determination in the medium. Rats were intraperitoneally injected with CCl4 for and the differentiated cells were injected into rat spleen. Histopathological and immunohistochemical analyses were performed. Liver functions were serologically and pathologically determined. Quantitative real-time-polymerase chain reaction was implemented to clarify the treatment procedure of liver cirrhosis. In vitro-differentiated hepatocyte-like cells were positive for all examined hepatic markers. SHED-derived hepatocyte transplantation eliminated liver fibrosis and restored liver structure in rats. Liver immunohistochemical analyses showed the presence of human-specific hepatic markers, i.e., a large amount of human hepatic cells were very active in the liver and spleen. Serological tests revealed significant liver function recovery in the transplantation group. Expression of genes promoting fibrosis increased after cirrhosis induction but was suppressed after transplantation. Our results suggest that xenotransplantation of hepatocyte-like cells of human origin can treat cirrhosis. Moreover, cell-based therapy of chronic liver conditions may be an effective option.


Cell transplantation Liver cirrhosis Tooth pulp stem cells Hepatic differentiation Hydrogen sulfide 



This study was funded by the Nippon Dental University. We also thank Masanori Nasu and Tetsuro Horie, Research Center for Odontology, School of Life Dentistry, Nippon Dental University.


This study was partially funded by Research Project No. 3 from Nippon Dental University, Tokyo, Japan.

Compliance with ethical standards

Conflict of interest

The authors have no competing interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee of Nippon Dental University School of Life Dentistry at Tokyo as well as the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants and their parents/LAR included in the study. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.


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Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Tomomi Yokoyama
    • 1
  • Hiromi Yagi Mendoza
    • 1
  • Tomoko Tanaka
    • 1
  • Hisataka Ii
    • 1
  • Riya Takano
    • 1
  • Ken Yaegaki
    • 1
    Email author
  • Hiroshi Ishikawa
    • 1
    • 2
  1. 1.Department of Oral HealthThe Nippon Dental University School of Life Dentistry at TokyoTokyoJapan
  2. 2.Laboratory of Clinical Regenerative Medicine, Department of Neurosurgery, Faculty of MedicineUniversity of Tsukuba, Laboratory of Advanced Research D # 326TsukubaJapan

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