Transplantation of chemically-induced liver progenitor cells ameliorates hepatic fibrosis in mice with diet-induced nonalcoholic steatohepatitis

Murakami, Sakae; Soyama, Akihiko; Miyamoto, Daisuke; Hara, Takanobu; Matsuguma, Kunihito; Imamura, Hajime; Matsushima, Hajime; Tanaka, Takayuki; Maruya, Yasuhiro; Adachi, Tomohiko; Miuma, Satoshi; Hidaka, Masaaki; Kanetaka, Kengo; Ochiya, Takahiro; Eguchi, Susumu

doi:10.1016/j.reth.2022.11.001

Cited by 6 publications

(3 citation statements)

References 29 publications

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“…14 The administration of CLiPs has been reported to promote regeneration in a CCl4-impaired liver model and inhibit fibrosis in a diet-induced nonalcoholic steatohepatitis model. 15 Thus, CLiPs may be very useful as a therapeutic tool for impaired liver.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the use of CLiPs leads to minimal concern about malignant transformation or other unpredictable risks because genetic modification is not required 14 . The administration of CLiPs has been reported to promote regeneration in a CCl4‐impaired liver model and inhibit fibrosis in a diet‐induced nonalcoholic steatohepatitis model 15 . Thus, CLiPs may be very useful as a therapeutic tool for impaired liver.…”

Section: Discussionmentioning

confidence: 99%

“…These cells have been designated as chemically induced liver progenitors (CLiPs) 14 . Considering the reported effectiveness of CLiP transplantation in injured livers of urokinase‐type plasminogen activator transgenic mice crossed with severe combined immunodeficiency disease mice 14 and a mouse model of diet‐induced nonalcoholic steatohepatitis, 15 this study was conducted with the aim of elucidating the efficacy of CLiPs for enhancing liver regeneration in aged livers, using a mouse model.…”

Section: Introductionmentioning

confidence: 99%

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Improvement in aged liver regeneration using cell transplantation with chemically induced liver progenitors

Matsuguma,

Hara,

Miyamoto

et al. 2024

J Hepato Biliary Pancreat

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BackgroundA decrease in the regenerative capacity of age‐damaged liver tissue has been reported. Liver progenitor cells may play an important role in the regeneration of injured livers. In the present study we aimed to investigate improvements in the regenerative capacity of age‐damaged livers using chemically induced liver progenitors (CLiPs) derived from mature hepatocytes.MethodsOld (>90 weeks) and young (<20 weeks) mice underwent 70% hepatectomy, with or without trans‐splenic CLiP administration. The residual liver/bodyweight (LW/BW) ratio was measured on postoperative days 1 and 7, and changes in liver regeneration and histology were evaluated.ResultsAt 7 days post‐hepatectomy, LW/BW ratios were significantly better in CLiP‐treated old mice than in untreated old mice (p = .02). By contrast, no effect of CLiP transplantation was observed in young mice (p = .62). Immunofluorescence staining of liver tissue after CLiP administration showed an increase in Ki67‐positive cells (p < .01). Flow cytometry analysis of green fluorescent protein‐labeled CLiPs indicated that transplanted CLiPs differentiated into mature hepatocytes and were present in the recipient liver.ConclusionsCLiP transplantation appears to ameliorate the age‐related decline in liver regeneration in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Improvement in aged liver regeneration using cell transplantation with chemically induced liver progenitors

Matsuguma,

Hara,

Miyamoto

et al. 2024

J Hepato Biliary Pancreat

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Efficacy of chemically induced human hepatic progenitor cells from diseased liver against nonalcoholic steatohepatitis model

Miyamoto,

Matsuguma,

Nagai

et al. 2024

J Hepato Biliary Pancreat

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BackgroundNumerous chemical reprogramming techniques have been reported, rendering them applicable to regenerative medicine research. The aim of our study was to evaluate the therapeutic potential of human CLiP derived from clinical specimens transplanted into a nonalcoholic steatohepatitis (NASH) mouse model of liver fibrosis.MethodsWe successfully generated chemically induced liver progenitor (CLiP), which exhibited progenitor‐like characteristics, through stimulation with low‐molecular‐weight compounds. We elucidated their cell differentiation ability and therapeutic effects. However, the therapeutic efficacy of human CLiP generated from clinical samples on liver fibrosis, such as liver cirrhosis, remains unproven.ResultsFollowing a 4 week period, transplanted human CLiP in the NASH model differentiated into mature hepatocytes and demonstrated suppressive effects on liver injury markers (i.e., aspartate transaminase and alanine transaminase). Although genes related to inflammation and fat deposition did not change in the human CLiP transplantation group, liver fibrosis‐related factors (Acta2 and Col1A1) showed suppressive effects on gene expression following transplantation, with approximately a 60% reduction in collagen fibers. Importantly, human CLiP could be efficiently induced from hepatocytes isolated from the cirrhotic liver, underscoring the feasibility of using autologous hepatocytes to produce human CLiP.ConclusionOur findings demonstrate the effectiveness of human CLiP transplantation as a viable cellular therapy for liver fibrosis, including NASH liver. These results hold promise for the development of liver antifibrosis therapy utilizing human CLiP within the field of liver regenerative medicine.

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Recent Advances in Regenerative Medicine of the Liver and Bile Duct System by Chemically Induced Liver Progenitor Cells (CLiPs) in Nagasaki Experience

Hidaka,

Miyamoto,

Eguchi

2023

Handbook of Stem Cell Applications

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Transplantation of chemically-induced liver progenitor cells ameliorates hepatic fibrosis in mice with diet-induced nonalcoholic steatohepatitis

Cited by 6 publications

References 29 publications

Improvement in aged liver regeneration using cell transplantation with chemically induced liver progenitors

Improvement in aged liver regeneration using cell transplantation with chemically induced liver progenitors

Efficacy of chemically induced human hepatic progenitor cells from diseased liver against nonalcoholic steatohepatitis model

Recent Advances in Regenerative Medicine of the Liver and Bile Duct System by Chemically Induced Liver Progenitor Cells (CLiPs) in Nagasaki Experience

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