Small molecule drugs promote repopulation of transplanted hepatocytes by stimulating cell dedifferentiation

Jiang, Mengmeng; Guo, Ren; Ai, Yan; Wang, Gang; Tang, Peilan; Jia, Xiaohui; He, Bin; Yuan, Qianting; Xie, Xin

doi:10.1016/j.jhepr.2023.100670

Cited by 4 publications

(4 citation statements)

References 41 publications

(52 reference statements)

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“…To investigate liver regeneration, two animal models were exploited. In the first model, partial hepatectomy (PHx) was performed in 6-week male mice as previously described 19 , 20 . For 2/3 PHx, the mice were anesthetized with 2% isoflurane and a midline incision was created to expose the xiphoid process.…”

Section: Methodsmentioning

confidence: 99%

Phosphatidic acid-enabled MKL1 contributes to liver regeneration: Translational implication in liver failure

Zhou,

Sun,

Chen

et al. 2024

Acta Pharmaceutica Sinica B

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Section: Methodsmentioning

confidence: 99%

Phosphatidic acid-enabled MKL1 contributes to liver regeneration: Translational implication in liver failure

Zhou,

Sun,

Chen

et al. 2024

Acta Pharmaceutica Sinica B

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“…All animal experiments were reviewed and approved by the Nanjing University Ethics Committee on Laboratory Animals. Partial hepatectomy was performed as previously described [ 21 , 22 ]. Acetaminophen (APAP) was dissolved in 1XPBS and the mice received a single injection at a dose of 300 mg/kg as previously described [ 23 , 24 ].…”

Section: Methodsmentioning

confidence: 99%

TRIB1 regulates liver regeneration by antagonizing the NRF2-mediated antioxidant response

et al. 2023

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Robust regenerative response post liver injuries facilitates the architectural and functional recovery of the liver. Intrahepatic redox homeostasis plays a key role in liver regeneration. In the present study, we investigated the contributory role of Tribbles homolog 1 (Trib1), a pseudokinase, in liver regeneration and the underlying mechanism. We report that Trib1 expression was transiently down-regulated in animal and cell models of liver regeneration. Further analysis revealed that hepatocyte growth factor (HGF) repressed Trib1 transcription by evicting liver X receptor (LXRα) from the Trib1 promoter. Knockdown of Trib1 enhanced whereas over-expression of Trib1 suppressed liver regeneration after partial hepatectomy in mice. Of interest, regulation of liver regenerative response by Trib1 coincided with alterations of intracellular ROS levels, GSH levels, and antioxidant genes. Transcriptional assays suggested that Trib1 influenced cellular redox status by attenuating nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Mechanistically, Trib1 interacted with the C-terminus of Nrf2 thus masking a potential nuclear localization signal (NLS) and blocking nuclear accumulation of Nrf2. Finally, correlation between Trib1 expression, Nrf2 nuclear localization, and cell proliferation was identified in liver specimens taken from patients with acute liver failure. In conclusion, our data unveil a novel pathway that depicts Trib1 as a critical link between intracellular redox homeostasis and cell proliferation in liver regeneration.

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“…However, the low efficiency of transplantation and limited proliferation of transplanted hepatocytes have hindered their clinical application [76]. A recent study found that hepatocytes transplanted into Fah‐deficient mice were reprogrammed into HPCs with enhanced proliferative capacity, suggesting that promoting hepatocyte reprogramming could aid in liver remodeling [77]. The study also found that small molecules promoting hepatocyte reprogramming in vitro , such as the ROCK inhibitor Y27632 and the WNT agonist CHIR99021, could improve the proliferation of transplanted hepatocytes in Fah −/− mice in vivo [77].…”

Section: In Vivo Hepatocyte Reprogramming For Clinical Therapymentioning

confidence: 99%

“…A recent study found that hepatocytes transplanted into Fah‐deficient mice were reprogrammed into HPCs with enhanced proliferative capacity, suggesting that promoting hepatocyte reprogramming could aid in liver remodeling [77]. The study also found that small molecules promoting hepatocyte reprogramming in vitro , such as the ROCK inhibitor Y27632 and the WNT agonist CHIR99021, could improve the proliferation of transplanted hepatocytes in Fah −/− mice in vivo [77]. Another approach to facilitate hepatocyte therapy is to promote HPC‐to‐hepatocyte differentiation in patients with advanced liver diseases.…”

Section: In Vivo Hepatocyte Reprogramming For Clinical Therapymentioning

confidence: 99%

Hepatocyte reprogramming in liver regeneration: Biological mechanisms and applications

Jiang,

Ren,

Belmonte

et al. 2023

The FEBS Journal

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The liver is one of the few organs that retain the capability to regenerate in adult mammals. This regeneration process is mainly facilitated by the dynamic behavior of hepatocytes, which are the major functional cell type in the liver. In response to liver injury, hepatocytes undergo remarkable alterations, such as reprogramming, wherein they lose their original identity and acquire properties from other cells. This phenomenon of hepatocyte reprogramming, coupled with hepatocyte expansion, plays a central role in liver regeneration, and its underlying mechanisms are complex and multifaceted. Understanding the fate of reprogrammed hepatocytes and the mechanisms of their conversion has significant implications for the development of innovative therapeutics for liver diseases. Herein, we review the plasticity of hepatocytes in response to various forms of liver injuries, with a focus on injury‐induced hepatocyte reprogramming. We provide a comprehensive summary of current knowledge on the molecular and cellular mechanisms governing hepatocyte reprogramming, specifically in the context of liver regeneration, providing insight into potential applications of this process in the treatment of liver disorders, including chronic liver diseases and liver cancer.

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Small molecule drugs promote repopulation of transplanted hepatocytes by stimulating cell dedifferentiation

Cited by 4 publications

References 41 publications

Phosphatidic acid-enabled MKL1 contributes to liver regeneration: Translational implication in liver failure

Phosphatidic acid-enabled MKL1 contributes to liver regeneration: Translational implication in liver failure

TRIB1 regulates liver regeneration by antagonizing the NRF2-mediated antioxidant response

Hepatocyte reprogramming in liver regeneration: Biological mechanisms and applications

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