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

Abstract

BackgroundWe 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.MethodsCanine 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.ResultsFour 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.ConclusionsWe 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.

Stem Cells in Veterinary Medicine—Current State and Treatment Options

“…IV application of autologous BMMSC significantly decreased the area of the liver fibrosis and improved liver function in the group receiving cells without any adverse side effects (221). Similarly to the IV, IA administration of BMMSC in a canine model of liver fibrosis was shown to be safe, but, interestingly, the effect on reducing levels of the liver enzymes in peripheral blood lasted longer with IA application of MSC (149). Autologous ADMSCs were also used repeatedly IV to treat 10 dogs with degenerative hepatopathy.…”

“…Similarly, IA injection of MSC was proven feasible with allogeneic equine BMMSC injected into the cranial tibial artery in horses, also without a tourniquet (148). Nishimura et al (149) also proved the safety and efficacy of the IA application of MSCs by administering autologous BMMSCs via the hepatic artery in a canine model of liver fibrosis. IP administration of MSCs is rarely used, but carries the potential to reach intraabdominal sites and appears relatively safe when used in cats (150).…”

Hyaluronan-Based Grafting Strategies for Liver Stem Cell Therapy and Tracking Methods

“…In humans, both the portal vein and the hepatic artery are considered as safe administration routes in liver cell therapy. Although further comparative studies are needed to define the best delivery method [51, 52], both routes have so far shown complications, such as hepatic artery dissection following hepatic artery infusion [53] and increased portal hypertensive bleeding upon portal vein infusion [54].…”

Trans-portal hepatic infusion of cultured bone marrow-derived mesenchymal stem cells in a steatohepatitis murine model

“…( 1 – 3 ) We have also used murine and canine models of liver fibrosis to evaluate the efficacy of cultured bone marrow-derived mesenchymal stem cells (BMSCs) in the treatment of decompensated liver cirrhosis and have developed a cultured BMSC hepatic artery infusion therapy that is less invasive and gives more sustained therapeutic effects. ( 4 – 6 )…”

“…(1)(2)(3) We have also used murine and canine models of liver fibrosis to evaluate the efficacy of cultured bone marrowderived mesenchymal stem cells (BMSCs) in the treatment of decompensated liver cirrhosis and have developed a cultured BMSC hepatic artery infusion therapy that is less invasive and gives more sustained therapeutic effects. (4)(5)(6) Given that the recent establishment of nucleoside/nucleotide analogs (NAs) and direct-acting antiviral (DAA) therapies has allowed us to control HBV and elucidate HCV, we anticipate an increasing number of liver cirrhosis cases caused by NASH. NASH-related liver cirrhosis and NASH-related hepatocellular carcinoma are already the second most common indications for liver transplantation in the United States; (7,8) thus, preventing NASH is an important topic.…”