IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner

Nishizawa, Hitoshi; Iguchi, Genzo; Fukuoka, Hidenori; Takahashi, Michiko; Suda, Kentaro; Bando, Hironori; Matsumoto, Ryusaku; Yoshida, Kenichi; Odake, Yukiko; Ogawa, Wataru; Takahashi, Yutaka

doi:10.1038/srep34605

Cited by 122 publications

(106 citation statements)

References 43 publications

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“…Besides, HGF and IGF‐1 play important roles in promoting hepatocyte proliferation and repairing tissue damage in the setting of liver injury. Moreover IGF‐1 can also decrease fibrosis and its expression was negatively associated with advanced fibrosis, which was consistent with a previous report . The hepatic tissue implant represents a promising alternative approach, notwithstanding the challenge in the time needed for cellular expansion in vivo.…”

Section: Discussionsupporting

confidence: 90%

Heterotopic vascularization and functionalization of implantable bio engineered hepatic tissue alleviates liver injury in rats

Yang

et al. 2019

Liver International

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Background The challenge of using bioengineered liver lies in sustaining the quantity of high‐quality hepatocytes and the vasculature for blood perfusion. We characterized the heparinization of a porcine decellularized liver scaffold (DLS) as a carrier to support hepatocyte angiogenesis, thereby developing functional and vascularized hepatic tissue useful to treat liver injury. Method The porcine DLS was obtained by the removal of cellular components and then subjected to heparinization by the end‐point attachment technique. The heparinized DLSs were recellularized with rat hepatocyte spheroids to construct engineered hepatic tissue. The hepatic tissue was heterotopically implanted in the omentum majus of a rat model with liver injury induced by carbon tetrachloride (CCl4). Results Hepatocyte spheroids in the heparinized DLS remained viable for at least 10 weeks in vivo. The entire scaffold was populated with hepatocytes and arranged well. The volume of the heparinized DLS group was expanded over 400‐fold. Liver‐specific functions such as albumin synthesis, glycogen storage and cytochrome P 3A4 activity were highly expressed in the hepatic tissue. In addition, endothelial cells were recruited, as shown by CD31 staining, and new blood vessels formed, as visualized by fluorescein isothiocyanate‐labelled dextran intravital confocal microscopy. The heparinized bioengineered hepatic tissue alleviated CCl4‐induced liver injury by regulating the deposition and degradation of the extracellular matrix. Conclusion Primary hepatocyte spheroids survived for an extended time on the heparinized DLS and expanded to generate vascularized and functional bioengineered hepatic tissue that can alleviate liver injury in rats.

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Section: Discussionsupporting

confidence: 90%

Heterotopic vascularization and functionalization of implantable bio engineered hepatic tissue alleviates liver injury in rats

Yang

et al. 2019

Liver International

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“…In contrast to its effects on growth and proliferation, reduced IGF‐I signaling has beneficial effects on longevity . Some reports demonstrated a cascade of IGF‐I action via ROS to induce cellular senescence in a p53‐dependent manner …”

Section: Discussionmentioning

confidence: 99%

Expansion of adipose tissue‐derived stromal cells at “physiologic” hypoxia attenuates replicative senescence

Ratushnyy

Lobanova

Буравкова

2017

Cell Biochemistry & Function

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Multipotent mesenchymal stromal cells are considered as a perspective tool in cell therapy and regenerative medicine. Unfortunately, autologous cell therapy does not always provide positive outcomes in elder donors, perhaps as a result of the alterations of stem cell compartments. The mechanisms of stem and progenitor cell senescence and the factors engaged are investigated intensively. In present paper, we elucidated the effects of tissue-related O on morphology, functions, and transcriptomic profile of adipose tissue-derived stromal cells (ASCs) in replicative senescence in vitro model. Replicatively senescent ASCs at ambient (20%) O (12-21 passages) demonstrated an increased average cell size, granularity, reactive oxygen species level, including anion superoxide, lysosomal compartment activity, and IL-6 production. Decreased ASC viability and proliferation, as well as the change of more than 10 senescence-associated gene expression were detected (IGF1, CDKN1C, ID1, CCND1, etc). Long-term ASC expansion at low O (5%) revoked in part the replicative senescence-associated alterations.

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“…Similarly, Nishizawa et al showed that administration of human recombinant insulin‐like growth factor 1 (IGF1) attenuates steatosis, inflammation, and fibrosis in mice treated to develop NASH or cirrhosis and drives HSCs to senescence. Importantly, these beneficial effects of IGF1 administration were not observed in p53‐deficient mice …”

Section: The Role Of Senescence In Nafld/nashmentioning

confidence: 96%

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

et al. 2019

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In recent years, cellular senescence has generated a lot of interest among researchers because of its involvement in both the normal aging process and common human diseases. During senescence, cells undergo alterations that include telomere shortening, nuclear area enlargement, and genomic and mitochondrial DNA damage, leading to irreversible cell cycle arrest, and secretion of proinflammatory cytokines. Evidence suggests that the complex process of senescence is involved in the development of a plethora of chronic diseases including metabolic and inflammatory disorders and tumorigenesis. Recently, several human and animal studies have emphasized the involvement of senescence in the pathogenesis and development of liver steatosis including the progression to nonalcoholic steatohepatitis (NASH) as characterized by the additional emergence of inflammation, hepatocyte ballooning, and liver fibrosis. The development of nonalcoholic fatty liver disease (NAFLD) and its progression to NASH are commonly accompanied by several pathophysiological events including metabolic dysregulation and inflammatory phenomena occurring within the liver that may contribute to or derive from cellular senescence, implying that the latter may be both a stimulus and a consequence of the disease. Conclusion: In this review, we summarize the current literature on the impact of cellular senescence in NAFLD/NASH and discuss the effectiveness and safety of novel senolytic drugs and therapeutic options available to delay or treat the disease. Finally, we identify the open questions and issues to be addressed in the near future.

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IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner

Cited by 122 publications

References 43 publications

Heterotopic vascularization and functionalization of implantable bio engineered hepatic tissue alleviates liver injury in rats

Heterotopic vascularization and functionalization of implantable bio engineered hepatic tissue alleviates liver injury in rats

Expansion of adipose tissue‐derived stromal cells at “physiologic” hypoxia attenuates replicative senescence

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

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