Inhibition of the Notch Signaling Pathway Reduces the Differentiation of Hepatic Progenitor Cells into Cholangiocytes in Biliary Atresia

Mao, Yong-Zhong; Tang, Shaotao; Yang, Li; Li, Kang

doi:10.1159/000493290

Cited by 20 publications

(16 citation statements)

References 33 publications

(36 reference statements)

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“…Next, we analyzed the expression of genes related to the pathways targeted by each of the small molecules (S, Da, De and F) at day 5 of myotube differentiation. As shown in Figure 2—figure supplement 2A–D, we found significant differential expression of CEBPD and FKBP5 (De targets; Luedi et al, 2017; MacDougald et al, 1994; Pan et al, 2010; Pereira et al, 2014; Reddy et al, 2012; Scharf et al, 2011), HES1 and NOTCH2 (Da targets; Huang et al, 2011; Jarriault et al, 1995; Mao et al, 2018), COL1A1 and ID3 (S targets; Lehmann et al, 2018; Ramachandran et al, 2018; Sato et al, 2015) and PPARGC1A (F target; Charos et al, 2012; Martin et al, 2009; Sayasith et al, 2014). Of note, S/Da/De/F treatment also induced the maturation of PS cell-derived myotubes generated under transgene-free conditions (Xi et al, 2017) (Figure 2—figure supplement 3A–B).…”

Section: Resultsmentioning

confidence: 52%

Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

Selvaraj

Mondragón-González

et al. 2019

eLife

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Targeted differentiation of pluripotent stem (PS) cells into myotubes enables in vitro disease modeling of skeletal muscle diseases. Although various protocols achieve myogenic differentiation in vitro, resulting myotubes typically display an embryonic identity. This is a major hurdle for accurately recapitulating disease phenotypes in vitro, as disease commonly manifests at later stages of development. To address this problem, we identified four factors from a small molecule screen whose combinatorial treatment resulted in myotubes with enhanced maturation, as shown by the expression profile of myosin heavy chain isoforms, as well as the upregulation of genes related with muscle contractile function. These molecular changes were confirmed by global chromatin accessibility and transcriptome studies. Importantly, we also observed this maturation in three-dimensional muscle constructs, which displayed improved in vitro contractile force generation in response to electrical stimulus. Thus, we established a model for in vitro muscle maturation from PS cells.

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Section: Resultsmentioning

confidence: 52%

Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

Selvaraj

Mondragón-González

et al. 2019

eLife

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“…Notch signalling is activated early in BECs following hepatic injury. The Notch signalling pathway is essential for the formation of bile ducts from embryonic hepatoblasts (20,21) and is reactivated in adult bile duct regeneration where it directs BECs into a cholangiocyte lineage (9,22,23), therefore we sought to address whether Notch also regulates hepatocyte regeneration from BECs. We have previously described a mouse model of hepatic regeneration where large numbers of hepatocytes can be generated from BECs (2,17).…”

Section: Resultsmentioning

confidence: 99%

Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation

et al. 2021

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In the adult liver, a population of facultative progenitor cells called biliary epithelial cells (BECs) proliferate and differentiate into cholangiocytes and hepatocytes after injury, thereby restoring liver function. In mammalian models of chronic liver injury, Notch signaling is essential for bile duct formation from these cells. However, the continual proliferation of BECs and differentiation of hepatocytes in these models have limited their use for determining whether Notch signaling is required for BECs to replenish hepatocytes after injury in the mammalian liver. Here, we used a temporally restricted model of hepatic repair in which large-scale hepatocyte injury and regeneration are initiated through the acute loss of Mdm2 in hepatocytes, resulting in the rapid, coordinated proliferation of BECs. We found that transient, early activation of Notch1- and Notch3-mediated signaling and entrance into the cell cycle preceded the phenotypic expansion of BECs into hepatocytes. Notch inhibition reduced BEC proliferation, which resulted in failure of BECs to differentiate into hepatocytes, indicating that Notch-dependent expansion of BECs is essential for hepatocyte regeneration. Notch signaling increased the abundance of the insulin-like growth factor 1 receptor (IGF1R) in BECs, and activating IGFR signaling increased BEC numbers but suppressed BEC differentiation into hepatocytes. These results suggest that different signaling mechanisms control BEC expansion and hepatocyte differentiation.

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“…They can provide pro-mitogenic factors such as HGF, TGF-β, TNF-α, and IL-6 [ 21 ]. More importantly, activation of the Notch signaling pathway by HSC and Wnt/β-catenin signaling pathway was vital for the differentiation of HPCs [ 24 , 25 ]. In contrast to 10 wpi, HPCs increased slightly at 6 wpi, which was an acute stage for an infection in mice.…”

Section: Discussionmentioning

confidence: 99%

Hepatic progenitor cells promote the repair of schistosomiasis liver injury by inhibiting IL-33 secretion in mice

Zhang

et al. 2021

Stem Cell Res Ther

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Background Hepatic schistosomiasis, a chronic liver injury induced by long-term Schistosoma japonicum (S. japonicum) infection, is characterized by egg granulomas and fibrotic pathology. Hepatic progenitor cells (HPCs), which are nearly absent or quiescent in normal liver, play vital roles in chronic and severe liver injury. But their role in the progression of liver injury during infection remains unknown. Methods In this study, the hepatic egg granulomas, fibrosis and proliferation of HPCs were analyzed in the mice model of S. japonicum infection at different infectious stages. For validating the role of HPCs in hepatic injury, tumor necrosis factor-like-weak inducer of apoptosis (TWEAK) and TWEAK blocking antibody were used to manipulate the proliferation of HPCs in wild-type and IL-33−/− mice infected with S. japonicum. Results We found that the proliferation of HPCs was accompanied by inflammatory granulomas and fibrosis formation. HPCs expansion promoted liver regeneration and inhibited inflammatory egg granulomas, as well as the deposition of fibrotic collagen. Interestingly, the expression of IL-33 was negatively associated with HPCs’ expansion. There were no obvious differences of liver injury caused by infection between wild-type and IL-33−/− mice with HPCs’ expansion. However, liver injury was more attenuated in IL-33−/− mice than wild-type mice when the proliferation of HPCs was inhibited by anti-TWEAK. Conclusions Our data uncovered a protective role of HPCs in hepatic schistosomiasis in an IL-33-dependent manner, which might provide a promising progenitor cell therapy for hepatic schistosomiasis.

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Inhibition of the Notch Signaling Pathway Reduces the Differentiation of Hepatic Progenitor Cells into Cholangiocytes in Biliary Atresia

Cited by 20 publications

References 33 publications

Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes

Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation

Hepatic progenitor cells promote the repair of schistosomiasis liver injury by inhibiting IL-33 secretion in mice

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