Report of research results:Development of a novel therapy for treating acute liver failure using M2 macrophages inducers identified from the stem cells of human exfoliated deciduous teeth

2017-3-14

Corresponding authors

Akihito Yamamoto(Department of Oral histology (Tissue regeneration from 1st of April 2017), Institute of Biomedical Science, Tokushima University Graduate School)

 

Title

Development of a novel therapy for treating acute liver failure using M2 macrophages inducers identified from the stem cells of human exfoliated deciduous teeth

 

Research member

  • Takanori Ito(Department of Gastroenterology and Hepatology of Nagoya University Graduate School of Medicine)
  • Masatoshi Ishigami(Department of Gastroenterology and Hepatology of Nagoya University Graduate School of Medicine)
  • Yoshiki Hirooka(Department of Gastroenterology and Hepatology of Nagoya University Graduate School of Medicine)
  • Hidemi Goto(Department of Gastroenterology and Hepatology of Nagoya University Graduate School of Medicine)
  • Tetsuya Ishikawa(Department of Gastroenterology and Hepatology of Nagoya University Graduate School of Medicine)
  • Yoshihiro Matsushita(Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine)
  • Marina Hirata(Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine)
  • Kohki Matsubara(Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine)
  • Hideharu Hibi(Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine)
  • Minoru Ueda(Department of Oral and Maxillofacial Surgery of Nagoya University Graduate School of Medicine)

 

Summary

Professor Akihito Yamamoto (Department of Tissue regeneration (former Oral histology), Institute of Biomedical Science, Tokushima University Graduate School and Assistant Professor Masatoshi Ishigami, Department of Gastroenterology and Hepatology of Nagoya University Graduate School of Medicine found that a single intravenous administration of monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (sSiglec-9), identified from stem cells derived from human exfoliated deciduous teeth (SHED), synergistically induced anti-inflammatory/tissue-regenerative M2 macrophages, and markedly improved hepatic injury and survival rate after acute liver failure (ALF). Our data suggest that MCP-1 and sSiglec-9 may be a novel therapeutic strategy for treating ALF patients. This study has been published in Scientific Reports on the 8th of March 2017.

 

Research Background

ALF induced by various causes (e.g. drugs, hepatitis viruses, autoimmune hepatitis) is unfavorable and intractable liver disease that is characterized by massive hepatocyte destruction and an uncontrolled inflammatory response. Although there are some supportive treatments, such as blood purification, liver transplantation is currently the only available treatment in progressive liver failure. However, its application is limited due to the shortage of donors and exorbitant cost. Therefore, alternative treatments for patients with ALF are urgently needed. We previously reported that a single intravenous administration of the conditioned medium of SHED (SHED-CM) improved rat ALF model without the cell-transplantation. However, it was unclear which among the various factors derived from SHED are responsible for ALF recovery. Here, we investigated the therapeutic activity of MCP-1/sSiglec-9, a major component of SHED-CM, in rat ALF model.

 

Research Results

Rat ALF was induced by the intraperitoneal injection of D-Gal. The survival rate of this model, a week after D-Gal injection, was less than 30%. A single intravenous administration of MCP-1/sSiglec-9, after onset of ALF markedly reduced liver damage and improved the survival rates to more than 90%. MCP-1/sSiglec-9 treatment synergistically suppressed tissue-destructive pro-inflammatory M1 circumstances, but induced the tissue-regenerating M2 one. Notably, depletion of M2 macrophages abolished MCP-1/sSiglec-9-mediated restoration hepatic function and improvement of the survival rate. Taken together, the unique combination of MCP-1/sSiglec-9 ameliorates rat ALF by inhibiting hepatocellular apoptosis and promoting liver regeneration through the induction of anti-inflammatory/tissue-repairing M2 macrophages.

 

Research Summary and Future Perspective

Our data suggest that MCP-1 and sSiglec-9 may be a promising therapeutic strategy for ALF. The goal of our study is to develop the novel anti-autoimmune drug based on the MCP-1 and sSiglec-9.

 

Fig.1Fig.1

 

Publication

Takanori Ito, Masatoshi Ishigami, Yoshihiro Matsushita, Marina Hirata, Kohki Matsubara, Tetsuya Ishikawa, Hideharu Hibi, Minoru Ueda, Yoshiki Hirooka, Hidemi Goto, Akihito Yamamoto. Secreted Ectodomain of SIGLEC-9 and MCP-1 Synergistically Improve Acute Liver Failure in Rats by Altering Macrophage Polarity. Scientific Reports

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