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.
Highlights
Four weeks after infusing BM-derived mesenchymal stem cells (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 indocyanine green (ICG) t1/2
Liver cirrhosis represents the advanced stage of liver fibrosis, presenting as regenerative nodules surrounded by fibrotic bands that develop in response to chronic liver injury [1,2,3]
In an effort to expand the applicability of autologous BM cell infusion (ABMi) therapy, we developed a less invasive method for liver regeneration therapy using autologous bone marrow (BM)-derived mesenchymal stem cells (BMSCs) cultured from small amounts of BM fluid aspirated under local anesthesia
Summary
Liver cirrhosis represents the advanced stage of liver fibrosis, presenting as regenerative nodules surrounded by fibrotic bands that develop in response to chronic liver injury [1,2,3]. Before human clinical trials can be considered, the safety and efficacy of cultured autologous BMSC infusion must be confirmed in medium-to-large animals To this end, we previously established a useful canine liver fibrosis model generated through the repeated administration of carbon tetrachloride (CCl4) through a catheter for 10 weeks. We previously established a useful canine liver fibrosis model generated through the repeated administration of carbon tetrachloride (CCl4) through a catheter for 10 weeks Using this model, we found that peripheral venous infusion using cultured autologous BMSCs could improve liver fibrosis without adverse effects, suggesting that this could represent a less invasive therapeutic option [11]. 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). 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
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