Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells

Hirose, Yoshikazu; Itoh, Tohru; Miyajima, Atsushi

doi:10.1016/j.yexcr.2009.06.018

Cited by 56 publications

(38 citation statements)

References 47 publications

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“…Activation of the Hedgehog signaling pathway is important for the proliferation and survival of cholangiocarcinoma [55]. Hedgehog also promotes the proliferation of hepatic progenitor cells [56]. Treatment of a cholangiocarcinoma cell line with a Hedgehog pathway inhibitor (i.e., cyclopamine) decreased cell proliferation and arrested the cell cycle at the G1 phase [55].…”

Section: Hedgehog Pathwaymentioning

confidence: 99%

Recent advances in cancer stem cell research for cholangiocarcinoma

Kokuryo

Yokoyama

Nagino

2012

J Hepato Biliary Pancreat

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Cancer stem cells have been identified as cells with the capacity to self‐renew and differentiate into multiple lineages of human malignancies. Cholangiocarcinoma is one of the most difficult intra‐abdominal malignancies that can be treated using a surgical approach. Chemotherapy in addition to surgery is necessary to improve patient survival. However, its clinical benefit is limited, and, to date, no other effective anticancer drug is available for this disease. Several reports have shown the existence of cholangiocarcinoma stem cells. Cell surface antigens such as CD133, CD24, EpCAM, CD44, and others have been used to isolate cholangiocarcinoma stem cells. In general, enhanced expression of these markers in resected specimens of cholangiocarcinoma was associated with malignant potential. Distinct and specific pathways are expected to be present in cancer stem cells compared to other cancer cells that have no stem cell properties. To date, reports showing possible signaling pathways in cholangiocarcinoma stem cells are limited. More research is anticipated. Targeting therapies for surface molecular markers or specific signaling pathways of cholangiocarcinoma stem cells may be important in order to change the clinical outcome of patients with this disease. However, no clinical trial has been performed so far. This review will focus on the markers and signaling pathways used to define cholangiocarcinoma stem cells. A novel therapeutic approach of targeting cholangiocarcinoma stem cells will also be discussed.

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Section: Hedgehog Pathwaymentioning

confidence: 99%

Recent advances in cancer stem cell research for cholangiocarcinoma

Kokuryo

Yokoyama

Nagino

2012

J Hepato Biliary Pancreat

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“…Mechanism that Underlies Proliferation Impairment in the Trisomic Condition Hedgehog signal activation is required for normal proliferation and differentiation in the intestine, 38 liver 39 and heart. 40 In the skin, the Shh pathway is crucial for the maintenance of the stem cell population, and for the regulation of hair follicle development.…”

Section: Dysregulation Of Ptch1 Expression May Be a Commonmentioning

confidence: 99%

Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression

Fuchs

Ciani

Guidi

et al. 2012

Laboratory Investigation

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Down syndrome (DS) is a genetic pathology due to the triplication of human chromosome 21. In addition to mental retardation, individuals with DS exhibit a large range of variable traits, including co-occurring congenital malformations. It is now clear that neurogenesis impairment underlies the typically reduced brain size and, hence, mental retardation in individuals with DS. The small body size and the constellation of congenital malformations in children with DS suggest that proliferation defects may involve peripheral tissues, in addition to the brain. The goal of the current study was to establish whether a generalized impairment of cell proliferation is a key feature of the trisomic condition. We used the Ts65Dn mouse, a widely used DS model, and examined proliferation in tissues with different embryological origin by 5-bromo-2-deoxyuridine immunohistochemistry. We found that 2-day-old (P2) Ts65Dn mice had notably fewer proliferating cells in the heart and liver, and in all proliferating niches of the skin and intestine. A reduced proliferation rate was still present in the intestine at P15. In all tissues, Ts65Dn mice had a similar number of apoptotic cells as euploid mice, indicating no unbalance in cell death. In the skin, liver and intestine of trisomic mice, we found a higher expression of patched1 (Ptch1), a receptor that represses the mitogenic sonic hedgehog (Shh) pathway. This suggests that Ptch1-dependent inhibition of Shh signaling may underlie proliferation impairment in trisomic peripheral tissues. In agreement with the widespread reduction in proliferation, neonate trisomic mice had a reduced body weight and this defect was still present at 30 days of age. Our findings show that, in all examined peripheral tissues, Ts65Dn mice exhibit a notable reduction in proliferation rate, suggesting that proliferation impairment may be a generalized defect of trisomic precursor cells.

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“…So, the different localization of ALR in the cells may be accordance with different functions during liver development. For example, the Sonic hedgehog (Shh), also a key gene in the regulation of liver development, was found to be highly expressed in the DLK + hepatoblasts from mouse fetal livers, and inhibition of Shh in vitro could potentiate the hepatic differentiation of hepatoblasts, which is similar to ALR [36]. However, the Shh specifically stimulated endocrine pancreatic development during the early stage of zebrafish development, with little effect on liver development [37,38].…”

Section: Discussionmentioning

confidence: 99%

Involvement of Hepatic Stimulator Substance in the Regulation of Hepatoblast Maturation into Hepatocytes In Vitro

Sun

Liu²,

An³

2014

Stem Cells and Development

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Hepatic stimulator substance (HSS), also known as augmenter of liver regeneration (ALR), acts as a hepatotrophic growth factor to promote liver regeneration after liver damage or partial hepatectomy. However, the expression and function of HSS during liver development in mammals remain largely unknown. In this work, the hepatoblasts were isolated from mice at embryonic day 13.5 (E13.5), and HSS expression and its role during hepatoblast maturation were investigated. The results showed that HSS expression was enhanced in the hepatoblasts compared with mouse primary hepatocytes. HSS expression (23 kDa) was significantly decreased if the hepatoblast maturation was induced by a combination of oncostatin M (OSM), dexamethasone (DEX), and hepatocyte growth factor (HGF). We also found that knockdown of HSS expression (mainly 23-kDa isoform) by siRNA promoted hepatoblast maturation and also activated the signal transducer and activator of transcription 3 (STAT3) phosphorylation levels. However, if STAT3 activity was blocked by a small-molecule inhibitor Stattic, then hepatocyte maturation could be abolished, suggesting that STAT3 was most likely a potential molecule responsible for HSS signaling. In summary, our results demonstrated for the first time that HSS might be an active factor participating in the regulation of liver development and hepatocyte maturation.

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Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells

Cited by 56 publications

References 47 publications

Recent advances in cancer stem cell research for cholangiocarcinoma

Recent advances in cancer stem cell research for cholangiocarcinoma

Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression

Involvement of Hepatic Stimulator Substance in the Regulation of Hepatoblast Maturation into Hepatocytes In Vitro

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