論文 - 齋藤　義正

Upper gastrointestinal triple stenosis in a patient with trisomy 17p syndrome: Case report and literature review

Ando H., Mori H., Takabayashi K., Matsuura N., Masaoka T., Matsuzaki J., Saito Y., Kato M., Kosaki K., Kanai T.

DEN Open 5 （ 1 ）  2025年04月

ISSN  2692-4609

　概要を見る

Upper gastrointestinal stenosis, which can be congenital or acquired, can lead to dysphagia. The association between trisomy 17p syndrome, a rare chromosomal abnormality, and upper gastrointestinal stenosis is unclear. A 20-year-old man diagnosed with trisomy 17p syndrome was referred to our department due to recurrent vomiting. Esophagogastroduodenoscopy revealed stenotic areas in the esophagus, stomach, and duodenum. The congenital gastrointestinal stenosis present in both the duodenum and esophagus suggested that the stasis and reflux of digestive fluids exacerbated stenosis in the stomach and esophagus. Gastric acid suppression therapy and endoscopic dilation of the esophagus and duodenum effectively resolved the patient's vomiting symptoms.

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Plasma extracellular vesicle microRNAs reflecting the therapeutic effect of the CBP/β-catenin inhibitor PRI-724 in patients with liver cirrhosis

Yoshida M., Matsuzaki J., Fujita K., Kimura M., Umezu T., Tokuda N., Yamaguchi T., Kuroda M., Ochiya T., Saito Y., Kimura K.

Scientific Reports 14 （ 1 ）  2024年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2045-2322

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There is an unmet need for antifibrotic therapies to prevent the progression of liver cirrhosis. Previously, we conducted an exploratory trial to assess the safety and antifibrotic efficacy of PRI-724, a selective CBP/β-catenin inhibitor, in patients with liver cirrhosis. PRI-724 was well tolerated and exerted a potential antifibrotic effect. Here, we investigated whether the profiles of circulating microRNAs packaged in extracellular vesicles (EV-miRNAs) are associated with responses to liver fibrosis treatments. Eighteen patients who received PRI-724 for 12 weeks in a phase 1/2a study were classified as responders (n = 10) or non-responders (n = 8) based on changes in liver stiffness. Plasma samples were obtained before and after PRI-724 administration and the levels of EV-miRNAs were analyzed. Three miRNAs (miR-6510-5p, miR-6772-5p, and miR-4261) were identified as predictors of response or non-response to PRI-724, and the levels of three other miRNAs (miR-939-3p, miR-887-3p, and miR-7112-5p) correlated with the efficacy of treatment. Expression of miR-887-3p was detected in hepatocytes and was decreased significantly in liver tissue following PRI-724 treatment. In addition, transfection of a miR-887-3p mimic activated hepatic stellate cells. Thus, decreases in the miR-887-3p level in blood may reflect recovery from liver fibroses in patients with liver cirrhosis treated with PRI-724, although further validation studies are warranted to confirm this.

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Intestinal metabolites predict treatment resistance of patients with depression and anxiety

Matsuzaki J., Kurokawa S., Iwamoto C., Miyaho K., Takamiya A., Ishii C., Hirayama A., Sanada K., Fukuda S., Mimura M., Kishimoto T., Saito Y.

Gut Pathogens 16 （ 1 ）  2024年12月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り,  ISSN  1757-4749

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Background: The impact of the gut microbiota on neuropsychiatric disorders has gained much attention in recent years; however, comprehensive data on the relationship between the gut microbiome and its metabolites and resistance to treatment for depression and anxiety is lacking. Here, we investigated intestinal metabolites in patients with depression and anxiety disorders, and their possible roles in treatment resistance. Results: We analyzed fecal metabolites and microbiomes in 34 participants with depression and anxiety disorders. Fecal samples were obtained three times for each participant during the treatment. Propensity score matching led us to analyze data from nine treatment responders and nine non-responders, and the results were validated in the residual sample sets. Using elastic net regression analysis, we identified several metabolites, including N-ε-acetyllysine; baseline levels of the former were low in responders (AUC = 0.86; 95% confidence interval, 0.69–1). In addition, fecal levels of N-ε-acetyllysine were negatively associated with the abundance of Odoribacter. N-ε-acetyllysine levels increased as symptoms improved with treatment. Conclusion: Fecal N-ε-acetyllysine levels before treatment may be a predictive biomarker of treatment-refractory depression and anxiety. Odoribacter may play a role in the homeostasis of intestinal L-lysine levels. More attention should be paid to the importance of L-lysine metabolism in those with depression and anxiety.

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A comparative study on dietary diversity and gut microbial diversity in children with autism spectrum disorder, attention-deficit hyperactivity disorder, their neurotypical siblings, and non-related neurotypical volunteers: a cross-sectional study

Kurokawa S., Nomura K., Sanada K., Miyaho K., Ishii C., Fukuda S., Iwamoto C., Naraoka M., Yoneda S., Imafuku M., Matsuzaki J., Saito Y., Mimura M., Kishimoto T.

Journal of Child Psychology and Psychiatry and Allied Disciplines 65 （ 9 ） 1184 - 1195 2024年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00219630

　概要を見る

Background: Previous research has shown a significant link between gut microbiota in children with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). However, much remains unknown because of the heterogeneity of disorders and the potential confounders such as dietary patterns and control group variations. Methods: Children aged 6–12 years who had been clinically diagnosed with ASD and/or ADHD, their unaffected neurotypical siblings, and non-related neurotypical volunteers were recruited cross-sectionally. The ASD diagnosis was confirmed using the Autism Diagnostic Observation Schedule-2 (ADOS-2) in all patients, including those with ADHD. Standardized DNA extraction and sequencing methods were used to compare gut microbial alpha-diversity among the groups. Dietary diversity was calculated from a standardized dietary questionnaire form. We compared the difference in gut microbiome between patients with ASD and/or ADHD with neurotypical siblings and non-related neurotypical controls. Results: Ninety-eight subjects were included in the study (18 with ASD, 19 with ADHD, 20 with both ASD and ADHD, 13 neurotypical siblings, and 28 non-related neurotypical controls). The alpha-diversity indices, such as Chao 1 and Shannon index, showed a significant difference between the groups in a Linear mixed-effect model (F(4, 93) = 4.539, p =.02), (F(4, 93) = 3.185, p =.017), respectively. In a post-hoc pairwise comparison, patients with ASD had lower alpha-diversity compared with non-related controls after Bonferroni correction. Dietary diversity shown in Shannon index did not differ among the groups (F(4, 84) = 1.494, p =.211). Conclusions: Our study indicates disorder-specific microbiome differences in patients with ASD. In future research on gut microbiota in neurodevelopmental disorders, it is necessary to consider the impact of ASD and ADHD co-occurrence, and strictly control for background information such as diet, to elucidate the gut–microbiota interaction in ASD and ADHD for exploring the potential of therapeutic interventions.

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Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance

Calvisi D.F., Boulter L., Vaquero J., Saborowski A., Fabris L., Rodrigues P.M., Coulouarn C., Castro R.E., Segatto O., Raggi C., van der Laan L.J.W., Carpino G., Goeppert B., Roessler S., Kendall T.J., Evert M., Gonzalez-Sanchez E., Valle J.W., Vogel A., Bridgewater J., Borad M.J., Gores G.J., Roberts L.R., Marin J.J.G., Andersen J.B., Alvaro D., Forner A., Banales J.M., Cardinale V., Macias R.I.R., Vicent S., Chen X., Braconi C., Verstegen M.M.A., Fouassier L., Scheiter A., Selaru F.M., Evert K., Utpatel K., Broutier L., Cadamuro M., Huch M., Goldin R., Gradilone S.A., Saito Y.

Nature Reviews Gastroenterology and Hepatology 20 （ 7 ） 462 - 480 2023年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  17595045

　概要を見る

Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.

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Exploring the Role of C19MC on the Differentiation Status of IHCC Organoids by Inducible CRISPR/dCas9

Ye, ZX; Matsuzaki, J; Oikawa, C; Saito, Y

CANCER SCIENCE 114   129 - 129 2023年02月

ISSN  1347-9032

Tracking phenotypical changes provided by driver gene mutations of pancreatic cancer

Oikawa, C; Matsuzaki, J; Ochiya, T; Saito, Y

CANCER SCIENCE 114   1574 - 1574 2023年02月

ISSN  1347-9032

Tracking phenotypical changes provided by driver gene mutations of pancreatic cancer

Oikawa, C; Matsuzaki, J; Ochiya, T; Saito, Y

CANCER SCIENCE 114   1893 - 1893 2023年02月

ISSN  1347-9032

Exploring the Role of C19MC on the Differentiation Status of IHCC Organoids by Inducible CRISPR/dCas9

Ye, ZX; Matsuzaki, J; Oikawa, C; Saito, Y

CANCER SCIENCE 114   606 - 606 2023年02月

ISSN  1347-9032

Efficacy and safety of low-dose rifabutin-based 7-day triple therapy as a third- or later-line Helicobacter pylori eradication regimen

Inokuchi K., Mori H., Matsuzaki J., Hirata K., Harada Y., Saito Y., Suzuki H., Kanai T., Masaoka T.

Helicobacter （Helicobacter）  27 （ 4 ）  2022年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  10834389

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Background: Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects are concerning. This study assessed the efficacy and safety of 7-day rifabutin, amoxicillin, and vonoprazan triple therapy as third- or later-line treatment for H. pylori infection. Materials and Methods: Patients who did not respond to second-line therapy were enrolled. After H. pylori infection was confirmed with the culture method, the patients received rifabutin-containing triple therapy (20 mg vonoprazan b.i.d., 500 mg amoxicillin q.i.d., and 150 mg rifabutin q.d.) for 7 days. Twelve weeks after the eradication therapy, successful eradication was confirmed using a 13C urea breath test or the H. pylori stool antigen test. The results obtained from our previous study that reported a 10-day or 14-day esomeprazole based rifabutin-containing triple therapy as a third- or fourth-line rescue therapy treated patients were used as historical control. We determined the minimum inhibitory concentrations of amoxicillin and rifabutin. We also evaluated whether the patients were positive for the mutation of the rpoB gene. Results: Intention-to-treat and per-protocol analyses showed that our regimen resulted in a high eradication rate (91.2%, 95% CI: 84%–99% and 92.7%, 95% CI: 86%–100%, respectively). Adverse events occurred in 31.6% of the patients, and two patients discontinued the therapy. Conclusions: This is the first study to evaluate the efficacy and safety of a 7-day low-dose rifabutin-based triple therapy with vonoprazan and amoxicillin. Our results suggest that our regimen was effective and safe as a third- or later-line H. pylori eradication regimen. To clarify what component in this regimen are critical, subsequent studies using a factorial design (comparing vonoprazan-amoxicillin dual therapy vs. vonoprazan-rifabutin triple therapy) will be needed.

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Hepatobiliary tumor organoids for personalized medicine: a multicenter view on establishment, limitations, and future directions Comment

van Tienderen Gilles S., Li Ling, Broutier Laura, Saito Yoshimasa, Inacio Patricia, Huch Meritxell, Selaru Florin M., van der Laan Luc J. W., Verstegen Monique M. A.

CANCER CELL （Cancer Cell）  40 （ 3 ） 226 - 230 2022年03月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  ISSN  1535-6108

　概要を見る

Reliable establishment of tumor organoids is paramount to advance applications of organoid technology for personalized medicine. Here, we share our multi-center experience on initiation and tumorigenic confirmation of hepatobiliary cancer organoids. We discuss current concerns, propose potential solutions, and provide future perspectives for improvements in hepatobiliary cancer organoid establishment.

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Challenges for better diagnosis and management of pancreatic and biliary tract cancers focusing on blood biomarkers: A systematic review

Tominaga H., Matsuzaki J., Oikawa C., Toyoshima K., Manabe H., Ozawa E., Shimamura A., Yokoyama R., Serizawa Y., Ochiya T., Saito Y.

Cancers 13 （ 16 ）  2021年08月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り

　概要を見る

Background: pancreatic cancer (PCa) and biliary tract cancer (BTC) are cancers with a poor prognosis and few effective treatments. One of the reasons for this is late detection. Many researchers are tackling to develop non-invasive biomarkers for cancer, but few are specific for PCa or BTC. In addition, genetic abnormalities occur in cancer tissues, which ultimately affect the expression of various molecules. Therefore, it is important to identify molecules that are altered in PCa and BTC. For this systematic review, a systematic review of Medline and Embase to select biomarker studies of PCa and BTC patients was conducted. Results: after reviewing 72 studies, 79 biomarker candidates were identified, including 22 nucleic acids, 43 proteins, and 14 immune cell types. Of the 72 studies, 61 examined PCa, and 11 examined BTC. Conclusion: PCa and BTC are characterized by nucleic acid, protein, and immune cell profiles that are markedly different from those of healthy subjects. These altered molecules and cell subsets may serve as cancer-specific biomarkers, particularly in blood. Further studies are needed to better understand the diagnosis and prognosis of PCa and BTC.

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Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids

Marsee A., Roos F.J.M., Verstegen M.M.A., Roos F., Verstegen M., Clevers H., Vallier L., Takebe T., Huch M., Peng W.C., Forbes S., Lemaigre F., de Koning E., Gehart H., van der Laan L.J.W., Spee B., Boj S., Baptista P., Schneeberger K., Soroka C., Heim M., Nuciforo S., Zaret K., Saito Y., Lutolf M., Cardinale V., Simons B., van IJzendoorn S., Kamiya A., Chikada H., Wang S., Mun S.J., Son M.J., Onder T.T., Boyer J., Sato T., Georgakopoulos N., Meneses A., Broutier L., Boulter L., Grün D., IJzermans J., Artegiani B., van Boxtel R., Kuijk E., Carpino G., Peltz G., Banales J., Man N., Aloia L., LaRusso N., George G., Rimland C., Yeoh G., Grappin-Botton A., Stange D., Prior N., Tirnitz-Parker J.E.E., Andersson E., Braconi C., Hannan N., Lu W.Y., Strom S., Sancho-Bru P., Ogawa S., Corbo V., Lancaster M., Hu H., Fuchs S., Hendriks D., Forbes S.J.

Cell Stem Cell （Cell Stem Cell）  28 （ 5 ） 816 - 832 2021年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  19345909

　概要を見る

Hepatic, pancreatic, and biliary (HPB) organoids are powerful tools for studying development, disease, and regeneration. As organoid research expands, the need for clear definitions and nomenclature describing these systems also grows. To facilitate scientific communication and consistent interpretation, we revisit the concept of an organoid and introduce an intuitive classification system and nomenclature for describing these 3D structures through the consensus of experts in the field. To promote the standardization and validation of HPB organoids, we propose guidelines for establishing, characterizing, and benchmarking future systems. Finally, we address some of the major challenges to the clinical application of organoids.

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The effects of continuous and withdrawal voluntary wheel running exercise on the expression of senescence-related genes in the visceral adipose tissue of young mice

Kimura M., Suzuki S., Moriya A., Nogami K., Uchida R., Saito Y., Saito H.

International Journal of Molecular Sciences （International Journal of Molecular Sciences）  22 （ 1 ） 1 - 12 2021年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  16616596

　概要を見る

© 2020 by the authors. Obesity has become a global medical problem. The upregulation of senescence-related markers in adipose tissue may cause impairment of adipose tissue and disorders of systemic me-tabolism. Weight control through diet has been found to ameliorate senescence in the adipose tissue. Exercise is also important in maintaining a healthy lifestyle, however, very few researchers have examined the relationship between senescence-related markers in adipose tissue. Dietary restriction is also reported to have a legacy effect, wherein the effects are maintained for some periods after the termination of the intervention. However, very few researchers have examined the relationship between exercise and senescence-related markers in adipose tissue. Besides, there is no study on the long-term effects of exercise. Hence, we investigated whether the exercise could change the expression of senescence-related genes in the visceral adipose tissue of young mice and whether there was a legacy effect of exercise for 10 weeks after the termination of exercise. Four-week-old male ICR mice were assigned to one of the three groups: 20 weeks of sedentary condition, 20 weeks of voluntary wheel running exercise, or 10 weeks of exercise followed by 10 weeks of sedentary condition. The mice showed decreased expression in genes related to senescence and senescence-associated secretory phenotype, such as p53, p16, and IL-6, in the visceral adipose tissue in response to exercise. These effects were maintained for 10 weeks after the mice stopped exercising. Our study is the first report that exercise reduces the expression of senescence-related genes in the visceral adipose tissue of young mice, and that exercise causes the legacy effect.

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An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping

Kawasaki K., Toshimitsu K., Matano M., Fujita M., Fujii M., Togasaki K., Ebisudani T., Shimokawa M., Takano A., Takahashi S., Ohta Y., Nanki K., Igarashi R., Ishimaru K., Ishida H., Sukawa Y., Sugimoto S., Saito Y., Maejima K., Sasagawa S., Lee H., Kim H.G., Ha K., Hamamoto J., Fukunaga K., Maekawa A., Tanabe M., Ishihara S., Hamamoto Y., Yasuda H., Sekine S., Kudo A., Kitagawa Y., Kanai T., Nakagawa H., Sato T.

Cell 183 （ 5 ） 1420 - 1435.e21 2020年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00928674

　概要を見る

© 2020 Elsevier Inc. Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes. Gastroenteropancreatic neuroendocrine neoplasms are a rare but lethal cancer with a scarcity of clinically relevant models. Kawasaki et al. establish and characterize 25 organoid lines to identify molecular subtypes with genotype-phenotype mapping.

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Establishment and Long-Term Culture of Organoids Derived from Human Biliary Tract Carcinoma

Saito Y., Muramatsu T., Saito H.

STAR Protocols 1 （ 1 ） 100009 2020年06月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り

　概要を見る

This protocol is a procedure for establishment and culture of cancer and non-cancer organoids using tissues from biliary tract carcinoma (BTC) patients. These BTC organoids can be used for various biological analyses and drug screening. One challenge in establishing and culturing BTC organoids is non-cancer cells contaminating surgically resected tumor tissues form organoids concurrently with cancer organoids. Careful validation that the established organoids are cancer-derived is important. For complete details on the use and generation of this protocol, please refer to Saito et al. (2019) in the journal Cell Reports.

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Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging

Uchida R., Saito Y., Nogami K., Kajiyama Y., Suzuki Y., Kawase Y., Nakaoka T., Muramatsu T., Kimura M., Saito H.

npj Aging and Mechanisms of Disease 5 （ 1 ）  2019年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2018, The Author(s). To understand the molecular features underlying stem cell aging, we established intestinal epithelial organoids derived from both young and aged mice and investigated alterations in their senescence and epigenetic status. Senescence-related changes including accumulation of senescence-associated β-galactosidase and up-regulation of Cdkn1a (p21) by DNA demethylation were observed in intestinal epithelial organoids derived from aged mice. We also demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3 lysine 27, inducing suppression of Wnt signaling and a decrease of cell proliferation in organoids from aged mice. We further treated intestinal epithelial organoids from aged mice with nicotinamide mononucleotide (NMN), a key NAD + intermediate. As a result, the organoids showed a higher NAD + level, increased cell proliferative ability, activation of Lgr5 and suppression of senescence-associated genes, indicating that treatment with NMN could ameliorate senescence-related changes in intestinal epithelia. These findings suggest that organoids derived from aged animals could be a powerful research tool for investigating the molecular mechanisms underlying stem cell aging and for development of some form of anti-aging intervention, thus contributing to prolongation of healthy life expectancy.

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Glucose depletion enhances the stem cell phenotype and gemcitabine resistance of cholangiocarcinoma organoids through AKT phosphorylation and reactive oxygen species

Yoshikawa N., Saito Y., Manabe H., Nakaoka T., Uchida R., Furukawa R., Muramatsu T., Sugiyama Y., Kimura M., Saito H.

Cancers 11 （ 12 ）  2019年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Cancer cells are strongly dependent on the glycolytic pathway for generation of energy even under aerobic condition through a phenomenon known as the Warburg effect. Rapid proliferation of cancer cells is often accompanied by high glucose consumption and abnormal angiogenesis, which may lead to glucose depletion. In the present study, we investigated how cholangiocarcinoma cells adapt to glucose depletion using a 3D organoid culture system. We cultured organoids derived from cholangiocarcinoma under glucose-free condition and investigated cell proliferation, expression of stem cell markers and resistance to gemcitabine. Cholangiocarcinoma organoids cultured under glucose-free condition showed reduced proliferation but were able to survive. We also observed an increase in the expression of stem cell markers including LGR5 and enhancement of stem cell phenotypic characteristics such as resistance to gemcitabine through AKT phosphorylation and reactive oxygen species. These findings indicate that cholangiocarcinoma cells are able to adapt to glucose depletion through enhancement of their stem cell phenotype in response to changes in microenvironmental conditions.

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Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets

Lau D.K., Mouradov D., Wasenang W., Luk I.Y., Scott C.M., Williams D.S., Yeung Y.H., Limpaiboon T., Iatropoulos G.F., Jenkins L.J., Reehorst C.M., Chionh F., Nikfarjam M., Croagh D., Dhillon A.S., Weickhardt A.J., Muramatsu T., Saito Y., Tebbutt N.C., Sieber O.M., Mariadason J.M.

iScience 21   624 - 637 2019年11月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2019 The Author(s) Biological Sciences; Genetics; Genomics; Cancer

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Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes

Katsuda T., Matsuzaki J., Yamaguchi T., Yamada Y., Prieto-Vila M., Hosaka K., Takeuchi A., Saito Y., Ochiya T.

eLife 8 2019年08月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© Katsuda et al. Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.

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