Differentiation of Pancreatic Acinar Cells to Hepatocytes Requires an Intermediate Cell Type

Wu, Sung–Yu; Hsieh, Chi-Hsun; Wu, Ruei-Ren; Susanto, Jimmy; Liu, Tsung Ta; Shen, Chia–Rui; Chen, Yu; Su, Chien-Chang; Chang, Fang-Pei; Chang, Hsiao-Min; Tosh, David; Shen, Chia-Ning

doi:10.1053/j.gastro.2010.02.011

Cited by 19 publications

(20 citation statements)

References 34 publications

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“…This could be a C. elegans-specific feature: indeed, nuclear reprogramming from one cell type-specific gene expression programme to another could be a comparatively simple process in C. elegans because, for example, they lack DNA methylation, which impacts on gene expression (Bird, 2002). However, even though direct evidence is missing, BrdU staining during various cell type conversions in mammals has suggested that they too occur in the absence of cell division (Means et al, 2005;Wu et al, 2010;Zhou et al, 2008), indicating that the complexity of DNA or chromatin modifications is not an obstacle to nuclear reprogramming in the absence of cell division. Consistently, recent findings have shown that elevated cell division does not accelerate iPS derivation by increasing the overall efficiency of the process itself, but rather by increasing the probability of a stochastic reprogramming event (Hanna et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, although the detailed sequence is missing, direct cell type conversion of pancreatic acinar to ductal cells has been suspected to occur through an intermediary cellular stage (Doetsch, 2003;Means et al, 2005;Pastrana et al, 2009;Wu et al, 2010). Similarly, pancreatic cell-to-hepatocyte conversion, the formation of coronary arteries from venous cells and the conversion of astrocytes into neuroblasts during adult neurogenesis are also suspected to occur through an intermediate cell that is less differentiated (Doetsch, 2003;Means et al, 2005;Pastrana et al, 2009;Red-Horse et al, 2010;Wu et al, 2010). Thus, some features of the Y-to-PDA conversion highlighted in this study are most likely relevant to other organisms.…”

Section: Discussionmentioning

confidence: 99%

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Direct in vivo cellular reprogramming involves transition through discrete, non-pluripotent steps

et al. 2011

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SUMMARYCells can change identity during normal development, in response to tissue damage or defined artificial treatments, or during disease processes such as cancer. Strikingly, not only the reprogramming of tissue cells to an embryonic stem cell-like state, but also the direct conversion from one cell type to another have been described. Direct cell type conversion could represent an alternative strategy for cellular therapies. However, little is known about the actual cellular steps undertaken by a cell as it changes its identity and their possible consequences for the organism. Using an in vivo single-cell system of natural direct reprogramming, in which a C. elegans rectal cell transforms into a motoneuron, we present an in-depth analysis of the cellular transformations involved. We found that the reprogrammed cell transits through intermediate states during direct in vivo reprogramming. We identified and characterised a mutant in the conserved COE transcription factor UNC-3 in which this cellular transformation is blocked. We determined that complete erasure of initial identity first takes place, followed by stepwise, unc-3-dependent, redifferentiation into a motoneuron. Furthermore, unlike in vitro induced reprogramming, reversion to a dedifferentiated identity does not lead to an increase in cellular potential in a natural, in vivo context. Our findings suggest that direct cell type conversion occurs via successive steps, and that dedifferentiation can occur in the absence of cell division. Furthermore, our results suggest that mechanisms are in place in vivo to restrict cell potential during reprogramming, a finding with important implications for regenerative medicine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Direct in vivo cellular reprogramming involves transition through discrete, non-pluripotent steps

et al. 2011

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“…Elas-CreER transgenic mice were generated at the Level Transgenic Center (Taipei, Taiwan) as described in as our previous work [43]. Kras +/LSLG12D mice (B6;129-Kras2 <tm4Tyj>) bearing a Cre-dependent conditional knock-in mutation Kras G12D were imported from Mouse Models of Human Cancer Consortium [44].…”

Section: Methodsmentioning

confidence: 99%

Elevation of β-galactoside α2,6-sialyltransferase 1 in a fructose-responsive manner promotes pancreatic cancer metastasis

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of pancreatic cancer with clinical characteristics of local invasion and early metastasis. Recent cohort studies indicate high fructose intake is associated with an increase in pancreatic cancer risk. However, the mechanisms by which fructose promotes pancreatic tumorigenesis remain unclear. Herein, Kras+/LSLG12D mice were crossed with Elas-CreER transgenic mice to determine whether fructose intake directly contributes to tumor formation. Orthotopic tumor-xenograft experiments were performed to determine whether fructose substitution enhances the metastatic potential of PDAC cells. The mechanisms underlying the effects of fructose were explored by RNAseq analysis in combination with high-performance anion exchange chromatography. Dietary fructose was initially found to promote the development of aggressive pancreatic cancer in mice conditionally expressing KrasG12D in the adult pancreas. We further revealed that fructose substitution enhanced the metastatic potential of human PDAC cell via selective outgrowth of aggressive ABCG2-positive subpopulations and elevating N-acetylmannosamine levels that upregulated β-galactoside α2,6-sialyltransferase 1 (ST6Gal1), thereby promoting distant metastasis. Finally, we observed that PDAC patients expressing higher levels of ST6Gal1 and GLUT5 presented poorer prognosis compared to other groups. In conclusion, our findings have elucidated a crucial role of ST6Gal1 in regulating the invasiveness of PDACs in a fructose-responsive manner.

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“…Pancreata harvested from 14-wk-old elastase-CreERKras G12D mice (elastase-CreER ϫ LSL-Kras G12D ) (42,44) were used to develop 3D duct lesion histology. To examine early stage duct lesion formation, elastase-CreER-Kras G12D mice were injected with tamoxifen (Sigma, St. Louis, MO) at age 6 wk (2 mg/injection, three injections in 1 wk to induce Cre-mediated recombination), and duct lesion was allowed to develop for the next 7 wk.…”

Section: Methodsmentioning

confidence: 99%

PanIN-associated pericyte, glial, and islet remodeling in mice revealed by 3D pancreatic duct lesion histology

Lin

Peng

Shen

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Pericytes and glial cells are accessory cells of neurovascular networks, which have been reported to participate in scar formation after tissue injury. However, it remains unclear whether similar reactive cellular responses occur in pancreatic intraepithelial neoplasia (PanIN). In this study we developed three-dimensional (3D) duct lesion histology to investigate PanIN and the associated pericyte, glial, and islet remodeling. Transparent mouse pancreata with a Kras G12D mutation were used to develop 3D duct lesion histology. Deep-tissue, tile-scanning microscopy was performed to generate panoramic views of the diseased pancreas for global examination of early stage and advanced duct lesion formation. Fluorescence signals of ductal and neurovascular networks were simultaneously detected to reveal associated remodeling. Significantly, in Kras G12D -mutant mice, when the low-grade PanINs emerge, duct lesions appear as epithelial buds with perilesional pericyte and glial activation. When PanINs occur in large scale (induced by cerulein injections to the mutant mice), the 3D image data identifies 1) aggregation of PanINs in clusters in space; 2) overexpression of the pericyte marker NG2 in the PanIN microenvironment; and 3) epithelial in-growth to islets, forming the PanIN-islet complexes. Particularly, the PanIN-islet complexes associate with proliferating epithelial and stromal cells and receive substantial neurovascular supplies, making them landmarks in the atrophic lobe. Overall, perilesional pericyte and glial activation and formation of the PanIN-islet complex underline cellular heterogeneity in the duct lesion microenvironment. The results also illustrate the advantage of using 3D histology to reveal previously unknown details of neurovascular and endocrine links to the disease. 3D histology; Kras G12D mutation; optical clearing; pancreatic intraepithelial neoplasia; PanIN-islet complex

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Differentiation of Pancreatic Acinar Cells to Hepatocytes Requires an Intermediate Cell Type

Cited by 19 publications

References 34 publications

Direct in vivo cellular reprogramming involves transition through discrete, non-pluripotent steps

Direct in vivo cellular reprogramming involves transition through discrete, non-pluripotent steps

Elevation of β-galactoside α2,6-sialyltransferase 1 in a fructose-responsive manner promotes pancreatic cancer metastasis

PanIN-associated pericyte, glial, and islet remodeling in mice revealed by 3D pancreatic duct lesion histology

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