Preclinical efficacy and safety of encapsulated proliferating human hepatocyte organoids in treating liver failure.

Alginate-encapsulated hepatocyte transplantation is a promising strategy to treat liver failure. However, its clinical application was impeded by the lack of primary human hepatocytes and difficulty in controlling their quality. We previously reported proliferating human hepatocytes (ProliHHs). Here, quality-controlled ProliHHs were produced in mass and engineered as liver organoids to improve their maturity. Encapsulated ProliHHs liver organoids (eLO) were intraperitoneally transplanted to treat liver failure animals. Notably, eLO treatment increased the survival of mice with post-hepatectomy liver failure (PHLF) and ameliorated hyperammonemia and hypoglycemia by providing liver functions. Additionally, eLO treatment protected the gut from PHLF-augmented permeability and normalized the increased serum endotoxin and inflammatory response, which facilitated liver regeneration. The therapeutic effect of eLO was additionally proved in acetaminophen-induced liver failure. Furthermore, we performed assessments of toxicity and biodistribution, demonstrating that eLO had no adverse effects on animals and remained non-tumorigenic.

Reversal of liver failure using a bioartificial liver device implanted with clinical-grade human-induced hepatocytes.

Liver resection is the first-line treatment for primary liver cancers, providing the potential for a cure. However, concerns about post-hepatectomy liver failure (PHLF), a leading cause of death following extended liver resection, have restricted the population of eligible patients. Here, we engineered a clinical-grade bioartificial liver (BAL) device employing human-induced hepatocytes (hiHeps) manufactured under GMP conditions. In a porcine PHLF model, the hiHep-BAL treatment showed a remarkable survival benefit. On top of the supportive function, hiHep-BAL treatment restored functions, specifically ammonia detoxification, of the remnant liver and facilitated liver regeneration. Notably, an investigator-initiated study in seven patients with extended liver resection demonstrated that hiHep-BAL treatment was well tolerated and associated with improved liver function and liver regeneration, meeting the primary outcome of safety and feasibility. These encouraging results warrant further testing of hiHep-BAL for PHLF, the success of which would broaden the population of patients eligible for liver resection.

Dedifferentiation-associated inflammatory factors of long-term expanded human hepatocytes exacerbate their elimination by macrophages during liver engraftment.

BACKGROUND AND AIMS: Hepatocyte transplantation has been demonstrated to be effective to treat liver metabolic disease and acute liver failure. Nevertheless, the shortage of donor hepatocytes restrained its application in clinics. To expand human hepatocytes at a large scale, several dedifferentiation-based protocols have been established, including proliferating human hepatocytes (ProliHH). However, the decreased transplantation efficiency of these cells after long-term expansion largely impedes their application. APPROACH AND RESULTS: We found that accompanied with dedifferentiation, long-term cultured ProliHH (lc-ProliHH) up-regulated a panel of chemokines and cytokines related to innate immunity, which were referred to as dedifferentiation-associated inflammatory factors (DAIF). DAIF elicited excessive macrophage responses, accounting for the elimination of lc-ProliHH specifically during engraftment. Two possible strategies to increase ProliHH transplantation were then characterized. Blockage of innate immune response by dexamethasone reverted the engraftment and repopulation of lc-ProliHH to a level comparable to primary hepatocytes, resulting in improved liver function and a better survival of fumarylacetoacetate hydrolase-deficient mice. Alternatively, rematuration of lc-ProliHH as organoids reduced the expression of DAIF and led to markedly improved engraftment. CONCLUSIONS: These results revealed that lc-ProliHH triggers exacerbated macrophage activation by DAIF and provided potential solutions for clinical transplantation of lc-ProliHH.

Posterior Reversible Encephalopathy Syndrome Associated With Anlotinib: A Case Report and Literature Review.

Posterior reversible encephalopathy syndrome (PRES) is a relatively rare clinical disease, characterized by reversible subcortical vasogenic edema. Here, we present the first reported case of PRES induced by anlotinib, a multi-target tyrosine kinase inhibitor. A 56-year-old female patient with lung adenocarcinoma and bone metastasis experienced hypertension and mental confusion when she received anti-angiogenesis treatment. PRES was diagnosed after magnetic resonance of the patient's brain revealed hyperintensities bilaterally around the cerebellum, pons, fronto-parieto-occipital areas, and corona radiate. Diffusion-weighted imaging showed hyperintensities bilaterally in the parieto-occipital cortical regions. Subsequently, the patient was diagnosed with PRES, and remission was achieved with anti-hypertensive drugs. Six cases of rare adverse effects induced by anlotinib were reviewed in the literature. Since anlotinib has been widely applied as a novel third-line treatment in patients with non-small-cell lung cancer, the association between PRES and anlotinib would benefit neurologists and oncologists in future diagnoses and treatment.