Pancreatic exocrine enzyme-producing cell differentiation via embryoid bodies from human embryonic stem cells

Shirasawa, Sakiko; Yoshie, Susumu; Yue, Fengming; Ichikawa, Hinako; Yokoyama, Tetsuji; Nagai, Machiko; Tomotsune, Daihachiro; Hirayama, Masao; Sasaki, Katsunori

doi:10.1016/j.bbrc.2011.06.036

Cited by 13 publications

(12 citation statements)

References 28 publications

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“…A previous study in SCLC cell lines suggested that expression of ACY1 would be reduced to an undetectable level in SCLC (13) and similar results were observed in liver cancer (17). These results indicated that ACY1 expression would be reduced throughout the process of tumor progress.…”

Section: Discussionsupporting

confidence: 80%

“…These results all indicate that ACY1 functions via the ERK pathway. Furthermore, activation of ERK increases the expression of TGF-β, another important factor involved in tumor progress (13,(15)(16)(17), and TGF-β could therefore directly attenuate the immune system and promote tumor proliferation (13,17). Thus, decreased expression of TGF-β could lead to tumor inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…The thermocycling conditions were as follows, for a total of 40 cycles: Denaturing at 95˚C for 30 sec; annealing at 60˚C for 5 sec; and extension at 72˚C for 45 sec. The 2 -ΔΔCq method was used for the quantification of the PCR results (13,17,18).…”

Section: Methodsmentioning

confidence: 99%

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Study of the expression and function of ACY1 in patients with colorectal cancer

Liu

Cao

et al. 2017

Oncology Letters

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Abstract. Aminoacylase 1 (ACY1) is important for regulating the proliferation of numerous types of cancer. However, the expression and mechanisms underlying the function of ACY1 in colorectal cancer remain unclear. In order to investigate the expression and function of ACY1 in colorectal cancer, tumor tissue and blood samples were collected for analysis from 132 patients diagnosed with colorectal cancer. Reverse transcription-quantitative polymerase chain reaction analysis and western blotting identified significantly increased expression of ACY1 mRNA in colorectal tumor tissue (P<0.05 vs. adjacent normal tissue) and notably increased ACY1 protein levels. This ACY1 mRNA expression was found to be positively correlated with tumor stage. In addition, plasma ACY1 concentration was increased in patients with colorectal cancer compared with healthy controls. Furthermore, in vitro knockdown of ACY1 in human colorectal cancer HT-29 cells was shown to inhibit proliferation and increase apoptosis. This effect was found to be associated with the activation of ERK1 and TGF-β1 signaling. In conclusion, the results of the present study suggest that ACY1 promotes tumor progression, and thus may be a potential target for the diagnosis and treatment of colorectal cancer. IntroductionColorectal cancer, the third most common cancer worldwide, is a major public health issue in China and globally (1). Although advances have been made in surgical and medical treatments, ~40% of patients with colorectal cancer succumb to the cancer (2). The early diagnosis and assessment of tumors is an area of intense study; however, it is a complex issue. Previous studies indicate that tumor cells of different clinical stages may exhibit different expression levels of certain biomarkers, which could be used as a target for the diagnosis or treatment of the tumor (3-5). In addition, with ongoing and advancing research into tumor biology, new targets are being identified and studied, including aminoacylase 1 (ACY1) (6).ACY1 is a cytosolic enzyme that deacylates the α-acylated amino acid from the N-terminal peptide of intracellular proteins (6). Following this, terminal acetylated proteins are more stable (7-9). In addition to its function in scavenging N-acylated amino acids, ACY1 has been studied in a number of types of human cancer. In small cell lung cancer (SCLC), renal cell carcinoma and liver cancer ACY1 expression has been demonstrated to be significantly reduced (10-13), suggesting that ACY1 serves a role in inhibiting tumorigenesis. Limited studies have investigated the detailed function and mechanism of ACY1 in tumor proliferation, and certain previous studies have reported that activation of ERK 1/2 and expression of TGF-β may be implicated in this process (13-16). However, the role of ACY1 in gastrointestinal cancer remains unclear. In the present study, the function and regulation of ACY1 in colorectal cancer was investigated through analyzing clinical samples. Materials and methodsPatients and clinical specimens. In total, 160 patients ...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Study of the expression and function of ACY1 in patients with colorectal cancer

Liu

Cao

et al. 2017

Oncology Letters

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“…A previous ultrastructural study of mESCs has shown that there is a clear increase in the cytoplasmic volume when ESCs are differentiated as EBs; in addition, there is an increase in protein synthesis (Sampath et al, 2008). In addition, many other investigations have studied ultrastructural morphology of EBs, which differentiated into various committed cell types, including cardiomyocytes (Taha et al, 2012), endothelial cells (Festag et al, 2007), hepatocytes (Kuai et al, 2014), skeletal muscle cells (Kawagoe et al, 2011), pancreatic exocrine enzyme-producing cells (Shirasawa et al, 2011), and renal cells (Kramer et al, 2006).…”

Section: Introductionmentioning

confidence: 97%

Ultrastructural Characteristics of Three Undifferentiated Mouse Embryonic Stem Cell Lines and Their Differentiated Three-Dimensional Derivatives: A Comparative Study

Alharbi

Elsafadi²,

Mobarak³

et al. 2014

Cellular Reprogramming

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The fine structures of mouse embryonic stem cells (mESCs) grown as colonies and differentiated in three-dimensional (3D) culture as embryoid bodies (EBs) were analyzed by transmission electron microscopy. Undifferentiated mESCs expressed markers that proved their pluripotency. Differentiated EBs expressed different differentiation marker proteins from the three germ layers. The ultrastructure of mESCs revealed the presence of microvilli on the cell surfaces, large and deep infolded nuclei, low cytoplasm-to-nuclear ratios, frequent lipid droplets, nonprominent Golgi apparatus, and smooth endoplasmic reticulum. In addition, we found prominent juvenile mitochondria and free ribosomes-rich cytoplasm in mESCs. Ultrastructure of the differentiated mESCs as EBs showed different cell arrangements, which indicate the different stages of EB development and differentiation. The morphologies of BALB/c and 129 W9.5 EBs were very similar at day 4, whereas C57BL/6 EBs were distinct from the others at day 4. This finding suggested that differentiation of EBs from different cell lines occurs in the same pattern but not at the same rate. Conversely, the ultrastructure results of BALB/c and 129 W9.5 ESCs revealed differentiating features, such as the dilated profile of a rough endoplasmic reticulum. In addition, we found low expression levels of undifferentiated markers on the outer cells of BALB/c and 129 W9.5 mESC colonies, which suggests a faster differentiation potential.

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“…In this sense, one important aspect missing in many pancreatic differentiation protocols is to assess the extent of selectivity in cell lineage induction. In this regard, other studies have reported the expression of acinar markers from ESC by manipulating several developmental pathways already established for endocrine differentiation or without examining their role on endocrine gene expression [12], [13], [14], [15]. Therefore, progress in the knowledge of how acinar cells are formed during embryogenesis is essential for the improvement of strategies assessing ESC exocrine differentiation.…”

Section: Introductionmentioning

confidence: 99%

Directed Pancreatic Acinar Differentiation of Mouse Embryonic Stem Cells via Embryonic Signalling Molecules and Exocrine Transcription Factors

et al. 2013

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Pluripotent embryonic stem cells (ESC) are a promising cellular system for generating an unlimited source of tissue for the treatment of chronic diseases and valuable in vitro differentiation models for drug testing. Our aim was to direct differentiation of mouse ESC into pancreatic acinar cells, which play key roles in pancreatitis and pancreatic cancer. To that end, ESC were first differentiated as embryoid bodies and sequentially incubated with activin A, inhibitors of Sonic hedgehog (Shh) and bone morphogenetic protein (BMP) pathways, fibroblast growth factors (FGF) and retinoic acid (RA) in order to achieve a stepwise increase in the expression of mRNA transcripts encoding for endodermal and pancreatic progenitor markers. Subsequent plating in Matrigel® and concomitant modulation of FGF, glucocorticoid, and folllistatin signalling pathways involved in exocrine differentiation resulted in a significant increase of mRNAs encoding secretory enzymes and in the number of cells co-expressing their protein products. Also, pancreatic endocrine marker expression was down-regulated and accompanied by a significant reduction in the number of hormone-expressing cells with a limited presence of hepatic marker expressing-cells. These findings suggest a selective activation of the acinar differentiation program. The newly differentiated cells were able to release α-amylase and this feature was greatly improved by lentiviral-mediated expression of Rbpjl and Ptf1a, two transcription factors involved in the maximal production of digestive enzymes. This study provides a novel method to produce functional pancreatic exocrine cells from ESC.

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Pancreatic exocrine enzyme-producing cell differentiation via embryoid bodies from human embryonic stem cells

Cited by 13 publications

References 28 publications

Study of the expression and function of ACY1 in patients with colorectal cancer

Study of the expression and function of ACY1 in patients with colorectal cancer

Ultrastructural Characteristics of Three Undifferentiated Mouse Embryonic Stem Cell Lines and Their Differentiated Three-Dimensional Derivatives: A Comparative Study

Directed Pancreatic Acinar Differentiation of Mouse Embryonic Stem Cells via Embryonic Signalling Molecules and Exocrine Transcription Factors

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