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Therapeutic potential of spheroids of stem cells from human exfoliated deciduous teeth for chronic liver fibrosis and hemophilia A

Abstract

Purpose

Mesenchymal stem cell (MSC)-based cell therapies have emerged as a promising treatment option for various diseases. Due to the superior survival and higher differentiation efficiency, three-dimensional spheroid culture systems have been an important topic of MSC research. Stem cells from human exfoliated deciduous teeth (SHED) have been considered an ideal source of MSCs for regenerative medicine. Thus, in the present study, we introduce our newly developed method for fabricating SHED-based micro-hepatic tissues, and demonstrate the therapeutic effects of SHED-based micro-hepatic tissues in mouse disease models.

Methods

SHED-converted hepatocyte-like cells (SHED-HLCs) were used for fabricating spherical micro-hepatic tissues. The SHED-HLC-based spheroids were then transplanted both into the liver of mice with CCl4-induced chronic liver fibrosis and the kidney of factor VIII (F8)-knock-out mice. At 4 weeks after transplantation, the therapeutic efficacy was investigated.

Results

Intrahepatic transplantation of SHED-HLC-spheroids improved the liver dysfunction in association with anti-fibrosis effects in CCl4-treated mice. Transplanted SHED-converted cells were successfully engrafted in the recipient liver. Meanwhile, renal capsular transplantation of the SHED-HLC-spheroids significantly extended the bleeding time in F8-knock-out mice.

Conclusions

These findings suggest that SHED-HLC-based micro-hepatic tissues might be a promising source for treating pediatric refractory diseases, including chronic liver fibrosis and hemophilia A.

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Acknowledgements

We thank Mr. Brian Quinn for the English editing. We greatly thank Dr. Fatima Safira Alatas (Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University) for her great technical support to this work. This work was supported by Grants from the Japan Society for the Promotion Science, including Grant-in-Aid for Scientific Research (Grant number 16H02682, 17K11513 and 18K08598) and Grant-in-Aid for Early-Career Scientists (Grant number 18K16260) Finally, we thank Ms. Tomoko Yamazaki (Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University) to her kind support in this study.

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Authors

Contributions

YT and RY: generation, collection and assembly of data, interpretation of data, statistical analysis, and drafting of the manuscript; TY: conception and design of the study, generation, collection and assembly of data, interpretation of data, statistical analysis, drafting of the manuscript, critical revision of the manuscript, and study supervision; SS, HY, KK, KY, and TM: generation, collection and assembly of data; TT, conception and design, interpretation of data, critical revision of the manuscript, and study supervision. All the authors approved the final version of the manuscript.

Corresponding author

Correspondence to Takayoshi Yamaza.

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All the authors declare no competing financial interests.

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Takahashi, Y., Yuniartha, R., Yamaza, T. et al. Therapeutic potential of spheroids of stem cells from human exfoliated deciduous teeth for chronic liver fibrosis and hemophilia A. Pediatr Surg Int 35, 1379–1388 (2019). https://doi.org/10.1007/s00383-019-04564-4

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  • DOI: https://doi.org/10.1007/s00383-019-04564-4

Keywords

  • SHED
  • Spheroids
  • Transplantation
  • Chronic liver fibrosis
  • Hemophilia A