1: Development of an Efficient Culture Method for Hepatocyte Organoids Maintaining Metabolic Functions / 2: Exploration of Kidney-Immune-Metabolic Crosstalk Originating from Tubular DNA Damage: Revealing New Intersections Between Chronic Kidney Disease and Aging
Science of the Month - June 2025
1: Development of an Efficient Culture Method for Hepatocyte Organoids Maintaining Metabolic Functions
Igarashi R, Oda M, Okada R, Yano T, Takahashi S, Pastuhov S, Matano M, Masuda N, Togasaki K, Ohta Y, Sato S, Hishiki T, Suematsu M, Itoh M, Fujii M, Sato T.
While the liver has high regenerative capacity, the in vitro proliferation of adult hepatocytes has been limited. Furthermore, the proliferation process often leads to biliary metaplasia, causing the loss of hepatocyte traits within a few days, which made it difficult to reproduce functions in a test tube. In this study, we found that STAT3 activation by Oncostatin M induces more than a million-fold expansion of adult hepatocytes while suppressing biliary metaplasia, allowing proliferation while maintaining hepatocyte identity. "Human Hepatocyte Organoids (HHO)" can reproduce functional cellular states, including liver zonation, through hormone administration and fasting treatment. We established methods to evaluate diverse hepatocyte functions such as drug metabolism, protein synthesis, gluconeogenesis, urea production, and bile acid secretion in vitro, demonstrating that functions comparable to those in vivo are maintained for over three months. Differentiated HHOs also form bile canaliculi structurally similar to those in the living body. HHOs derived from infant hepatocytes successfully engrafted and proliferated in liver injury model mice. As in vitro disease models, we were able to evaluate the effects of therapeutic drugs for fatty liver disease and reproduce the pathology of OTC deficiency and G6PC deficiency through genome editing. HHOs with diverse functions are expected to be applied not only to basic research such as drug discovery and disease studies but also to clinical applications in drug metabolism toxicity testing and regenerative medicine.
(Department of Biochemistry: Toshiro Sato, Ryo Igarashi)
2: Exploration of Kidney-Immune-Metabolic Crosstalk Originating from Tubular DNA Damage: Revealing New Intersections Between Chronic Kidney Disease and Aging
Nishimura ES, Hishikawa A, Nakamichi R, Akashio R, Chikuma S, Hashiguchi A, Yoshimoto N, Hama EY, Maruki T, Itoh W, Yamaguchi S, Yoshino J, Itoh H, Hayashi K.
The number of patients with chronic kidney disease is increasing globally against the backdrop of an aging population, posing a problem by increasing the risk of not only cardiovascular disease but also all-cause mortality. In this study, we focused on proximal tubular epithelial cell damage, which is involved in the common pathway of renal injury progression. Our group previously reported that the degree of double-strand DNA damage in proximal tubular epithelial cells is associated with renal prognosis. In this study, we showed that DNA damage in proximal tubular epithelial cells causes systemic metabolic changes similar to metabolic aging—such as weight loss, loss of fat weight, ectopic fat deposition in the liver and heart, and glucose intolerance—mediated by the activation of inflammatory monocytes and macrophages through DNA methylation changes. The results of this study present a new aspect to the understanding of the cardio-renal-metabolic linkage that has recently garnered attention. By evaluating DNA damage in renal proximal tubular epithelial cells, it may be possible to estimate the progression of systemic metabolic aging and predict other organ damage, including cardiovascular complications. We also hope this will contribute to the development of new preventive and therapeutic strategies for kidney disease progression and the onset of complications targeting peripheral blood DNA methylation.
(Department of Nephrology, Endocrinology and Metabolism: Kaori Hayashi)
Other Published Papers
1: The trajectory of sedative adverse events caused by antipsychotics: a meta-analysis of individual participant data from randomised, placebo-controlled, clinical trials in acute phase schizophrenia.
Lancet Psychiatry.
Nomura N, Siafis S, Schneider-Thoma J, Brandt L, Park J, Efthimiou O, Priller J, Davis JM, Takeuchi H, Leucht S.
2: Macrotrabecular hepatocellular carcinoma: Unique immunovascular characteristics.
Hepatology.
Kurebayashi Y, Sakamoto M.