Liver regeneration therapy through the hepatic artery-infusion of cultured bone marrow cells in a canine liver fibrosis model

• Published in: PloS one 2019-01, Vol.14 (1), p.e0210588-e0210588
• Main Authors: Nishimura, Tatsuro, Takami, Taro, Sasaki, Ryo, Aibe, Yuki, Matsuda, Takashi, Fujisawa, Koichi, Matsumoto, Toshihiko, Yamamoto, Naoki, Tani, Kenji, Taura, Yasuho, Sakaida, Isao
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Autografts; Biology and Life Sciences; Blood; Bone marrow; Bone marrow cells; Bone Marrow Cells - cytology; Bone Marrow Transplantation - adverse effects; Carbon Tetrachloride; Care and treatment; Catheters; Cell adhesion & migration; Cells, Cultured; Cirrhosis; Computed tomography; Disease Models, Animal; Dog diseases; Dogs; Engineering and Technology; Female; Fibrosis; Gastroenterology; Gene Expression Regulation; Hepatic artery; Hepatic Artery - diagnostic imaging; Hepatic Artery - physiopathology; Hepatology; Indocyanine Green - metabolism; Infarction; Infusion; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Liver; Liver cirrhosis; Liver Cirrhosis - diagnostic imaging; Liver Cirrhosis - pathology; Liver Cirrhosis - physiopathology; Liver Cirrhosis - therapy; Liver Regeneration; Male; Medicine and Health Sciences; Mesenchymal stem cells; Mesenchyme; Regeneration; Research and Analysis Methods; Safety; Safety and security measures; Stem cells; Surgery; Surgical outcomes; Tomography, X-Ray Computed; Transplants & implants; Treatment outcome; University graduates; Veins; Veterinary medicine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0210588

We previously reported regenerative therapies for decompensated cirrhosis based on peripheral venous drip infusion using non-cultured whole bone marrow (BM) cells, or the less invasive cultured BM-derived mesenchymal stem cells (BMSCs). Here, we assessed the efficacy and safety of hepatic arterial infusion using cultured autologous BMSCs, comparing it with peripheral infusion, using our established canine liver fibrosis model. Canine BM cells were harvested and cultured, and the resultant BMSCs were returned to carbon tetrachloride (CCl4)-induced liver cirrhosis model canines via either a peripheral vein (Vein group) or hepatic artery (Artery group). A variety of assays were performed before and 4, 8, and 12 weeks after BMSC infusion, and liver fibrosis and indocyanine green (ICG) half-life (t1/2) were compared to those in a control group that received CCl4 but not BMSCs. The safety of this approach was evaluated by contrast-enhanced computed tomography (CT) and serial blood examinations after infusion. Four weeks after infusing BMSCs, a significant improvement was observed in the Vein group (n = 8) compared to outcome in the Control group (n = 10), along with a decrease in ICG t1/2. In the Artery group (n = 4), ICG t1/2 was significantly shorter than that in the Vein group at 8 weeks (Δt1/2: -3.8 ± 1.7 min vs. +0.4 ± 2.4 min; p < 0.01) and 12 weeks (Δt1/2: -4.2 ± 1.7 min vs. +0.4 ± 2.7 min; p < 0.01) after BMSC administration. Post-infusion contrast-enhanced CT showed no liver infarction, and blood tests showed no elevations in either serum lactate dehydrogenase concentrations or hypercoagulability. We confirmed the efficacy and safety of the hepatic arterial infusion of cultured autologous BMSCs using a canine model, thereby providing non-clinical proof-of-concept.