Our liver regeneration therapies using autologous bone marrow-derived cells for liver cirrhosis: current status and prospects

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Takami T1, Sakaida I1

1Department of Gastroenterology and Hepatology, Yamaguchi University, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan

Compared to patients with other etiologies, alcoholic liver cirrhotic patients at our hospital tend to be younger and have more severe conditions; additionally, they want to receive liver regeneration therapy and are willing to avoid alcohol. We reported the clinical efficacy and safety of autologous bone marrow (BM) cell infusion therapy as liver regeneration therapy for decompensated liver cirrhosis (LC), including alcoholic LC. Our study demonstrated the following: the dissolution of liver fibrosis is associated with collagenase expression from migrated BM cells in the damaged liver, followed by the activation of hepatic progenitor cells and the proliferation of hepatocytes, which improves liver functions and induces liver regeneration. Furthermore, less invasive liver regeneration therapy with the infusion of autologous BM-derived mesenchymal stem cells (BMSCs), which are cultured from a small amount of BM aspirate, promotes liver regeneration and is currently under development. A human clinical trial (no. NCT02327832) on patients with decompensated LC, including those with alcoholic LC, is being performed to assess the safety of the peripheral infusion of cultured autologous BMSCs. We previously reported that the frequent infusion of whole BM cells inhibits liver fibrosis and hepatocarcinogenesis in a model with LC with a higher potential of carcinogenesis, and the peripheral infusion of human cultured BMSCs reduces liver fibrosis in immunodeficient liver cirrhotic mice. Moreover, it was confirmed that the following factors contribute to the mechanism of liver fibrosis and hepatocarcinogenesis: reduced liver fibrosis by direct BMSC-derived collagenases, the continuous oxidative stress of hepatocytes by direct BMSC-derived exosomes, and induced collagenase-producing macrophages by BMSCs during cell-cell interaction. In addition, we originally developed a canine LC model and compared the levels of liver fibrosis and the indocyanine green half-life between hepatic arterial infusion and peripheral infusion to determine the optimum route for BMSC infusion, and develop a liver regeneration therapy with higher therapeutic effects. We confirmed better improvement and a more prolonged duration with hepatic arterial infusion than with peripheral infusion. Therefore, we are planning to perform a human clinical trial to assess the safety of hepatic artery infusion of cultured autologous BMSCs in patients with decompensated LC.