Biology subjects

Nishina, H.

Publications and source records attributed to Nishina, H..

3 recordsLinked to original sources

bioRxiv2026

The sympathetic nervous system initiates liver regeneration

Within hours of injury to the liver, signals from damaged hepatocytes activate Kupffer cells, inducing the production of inflammatory cytokines and proliferation of quiescent hepatocytes to regenerate the liver1,2. In humans, liver regenerative capacity declines with age3,4. However, the nature of the initial signals of liver regeneration and how they are affected during aging remain unclear. In this study, we leveraged "neuro-aging mice", in which neuronal function declines with age5, and discovered an essential role for intrahepatic sympathetic nerves in the early phase of liver regeneration. Upon liver injury in wild-type mice, there was a rapid, transient production of noradrenaline (NA) in the liver. This was abolished in neuro-aging mice who instead exhibited decreased metabolic capacity and fatal liver regeneration failure. NA coordinated the activity of multiple cell types by inducing expression of acute-response genes in hepatocytes and stimulating production of inflammatory cytokines such as IL-6 in Kupffer cells. These results identify a crucial role for the sympathetic nervous system and NA in liver regeneration. Further, they suggest that aging-related loss of this sympathetic nerve-NA regulatory axis reduces liver regenerative capacity.

physiology↗

bioRxiv2021

Hepatocytes with a phenotype of substantial CYP3A4 induction generated from drug-associated fulminant hepatitis-derived induced pluripotent stem cells

Hepatocyte-like cells (HLCs) generated from human pluripotent stem cells (PSCs) exhibit hepatocytic properties in vitro; however, their engraftment and functionality in vivo remain unsatisfactory. Despite optimization of differentiation protocols, HLCs did not engraft in a mouse model of liver injury. In contrast, organ-derived hepatocytes reproducibly formed colonies in the liver injury mouse model. As an extension of the phenomenon observed in hematopoietic stem cells giving rise to colonies within the spleen, commonly referred to as "colony-forming units in spleen (CFU-s", we hypothesize that "colony-forming units in liver (CFU-L)" serves as a reliable indicator of stemness, engraftment, and functionality of hepatocytes. The uniform expression of the randomly inactivated gene in a single colony, as reported by Sugahara et al. 2022, suggests that the colonies generated by isolated hepatocytes likely originate from a single cell. We, therefore, propose that CFU-L can be used to quantify the number of "hepatocytes that engraft and proliferate in vivo" as a quantitative assay for stem cells that utilize colony-forming ability, similar to that observed in hematopoietic stem cells.

cell biology↗

bioRxiv2020

Puromycin selection of cells with a high expression of the cytochrome P450 CYP3A4 gene activity from a patient with drug-induced liver injury (DILI) and their lifespan prolongation using a combination of CDK4R24C, cyclin D1 and TERT

Many drugs have the potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4), in hepatocytes. Hepatocytes can accurately evaluate drug-mediated CYP3A4 induction as the gold standard for in vitro hepatic toxicology test, but their lot variation is an issue to be solved. Only a limited number of immortalized hepatocyte cells have been reported. In this study, we generated an immortalized cell expressing CYP3A4 from a patient with drug-induced liver injury (DILI). To generate DILI-derived cells with a high expression of CYP3A4, we employed a three-step approach: 1. Differentiation of DILI-induced pluripotent stem cells (DILI-iPSCs); 2. Immortalization of the differentiated cells; 3. Selection of the cells with puromycin. We hypothesize that cells with a high expression of cytochrome P450 genes can survive even after exposure to cytotoxic antibiotics because of high drug-metabolism activity. Puromycin, one of the cytotoxic antibiotics, was used in this study because of its rapid cytocidal effect at a low concentration. Phenotypic studies in vitro revealed that the puromycin-selected cells (HepaSM or SI cells) constitutively expressed the CYP3A4 gene at an extremely high level, and continued to proliferate at least up to 34 population doublings for more than 250 days. The expression profiles were independent of population doublings. Drug-mediated induction test revealed that the cells significantly increased CYP3A4 after exposure to rifampicin, suggesting that the immortalized cells would serve as another useful source for in vitro examination of drug metabolism and CYP3A4 induction.

cell biology↗