Treatment of liver cirrhosis using hepatocyte-derived liver progenitor-like cells: a prospective, open-label, single-arm, safety trial
摘要
Liver transplantation remains constrained by the scarcity of donor organs and the risks inherent in the procedure, underscoring the urgent need for novel cirrhosis therapies. We developed a protocol to convert human primary hepatocytes into expandable hepatocyte-derived liver progenitor-like cells (HepLPCs), which secrete high levels of matrix metalloproteinases and hepatocyte growth factor. In a thioacetamide-induced rat model of cirrhosis, human HepLPCs demonstrated potent anti-fibrotic properties and promoted liver regeneration. Biodistribution studies revealed that most xenogenic HepLPCs were cleared from the body within one week, suggesting that their therapeutic benefits likely arise from paracrine signaling rather than long-term engraftment. We initiated a first-in-human clinical trial involving nine patients with cirrhosis to evaluate the feasibility and safety of HepLPCs. Preclinical toxicity assessments in 36 crab-eating macaques confirmed the safety of HepLPC treatment. In the clinical trial, nine patients (mean age: 53 years), primarily with HBV-related cirrhosis, received HepLPCs via trans-hepatic arterial infusion without immunosuppressants. No serious adverse event was observed, and the minor adverse events were consistent with those commonly seen in cirrhosis patients. The treatment was well tolerated, with no transfusion reactions or dose-limiting toxicities. While significant changes in Child-Pugh and MELD scores were not observed, some patients showed improvements in liver biochemical parameters, coagulation profiles, and portal hypertension indicators during the six-month follow-up. These findings indicate that HepLPC therapy is safe and feasible, offering a promising new strategy for treating cirrhosis. Further clinical trials are needed to assess its efficacy in patients with decompensated cirrhosis and acute-on-chronic liver failure.