Lineage Tracing Evidence for Transdifferentiation of Acinar to Duct Cells and Plasticity of Human Pancreas

Houbracken, Isabelle; Waele, Evelien De; Lardon, Jessy; Ling, Zhidong; Heimberg, Harry; Rooman, Ilse; Bouwens, Luc

doi:10.1053/j.gastro.2011.04.050

Cited by 123 publications

(154 citation statements)

References 39 publications

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“…After culturing epithelial explants for five days in the presence of TGF-α, cystic ductal epithelial structures formed that were positive for β-gal activity (71). Houbracken and colleagues very recently showed that human acinar cells display an equal amount of plasticity through lineage tracing (72). Interestingly, after one week of culture, almost all of the surviving acinar cells expressed ductal markers.…”

Section: Adm: Insights Into Ductal Cell Reprogramming and Neoplastic mentioning

confidence: 99%

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Pancreatic ductal cells in development, regeneration, and neoplasia

Reichert¹,

Rustgi²

2011

J. Clin. Invest.

215

189

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The pancreas is a complex organ comprised of three critical cell lineages: islet (endocrine), acinar, and ductal. This review will focus upon recent insights and advances in the biology of pancreatic ductal cells. In particular, emphasis will be placed upon the regulation of ductal cells by specific transcriptional factors during development as well as the underpinnings of acinar-ductal metaplasia as an important adaptive response during injury and regeneration. We also address the potential contributions of ductal cells to neoplastic transformation, specifically in pancreatic ductal adenocarcinoma.

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Section: Adm: Insights Into Ductal Cell Reprogramming and Neoplastic mentioning

confidence: 99%

“…Interestingly, after one week of culture, almost all of the surviving acinar cells expressed ductal markers. This could be prevented partially by inhibiting MAPK signaling (72).…”

Section: Adm: Insights Into Ductal Cell Reprogramming and Neoplastic mentioning

confidence: 99%

Pancreatic ductal cells in development, regeneration, and neoplasia

Reichert¹,

Rustgi²

2011

J. Clin. Invest.

215

189

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“…Primary acinar cell culture protocols were adapted from previous works (15,16). The cell lines 266-6 and AR42J-B13, the PDAC cell lines, and HEK293 cells were obtained from American Type Culture Collection (ATCC) Cell Biology Collection and used within 6 months between resuscitation and experimentation.…”

Section: Cell Culturesmentioning

confidence: 99%

“…Functional significance of nuclear-to-cytoplasmic shuttling of Sirt1 in ADM We reported before on rodent and human exocrine cell cultures (4,15,16), the latter specifically providing insights into onset of ADM that cannot be obtained from in vivo (clinical) samples. Cells of non-acinar origin that also can contribute to the in vivo ADM-type lesions are likely not represented in the in vitro models.…”

Section: Sirt1 and Dbc1 Expression In Normal Exocrine Tissue And Admmentioning

confidence: 99%

Sirtuin-1 Regulates Acinar-to-Ductal Metaplasia and Supports Cancer Cell Viability in Pancreatic Cancer

et al. 2013

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The exocrine pancreas can undergo acinar-to-ductal metaplasia (ADM), as in the case of pancreatitis where precursor lesions of pancreatic ductal adenocarcinoma (PDAC) can arise. The NAD þ -dependent protein deacetylase Sirtuin-1 (Sirt1) has been implicated in carcinogenesis with dual roles depending on its subcellular localization. In this study, we examined the expression and the role of Sirt1 in different stages of pancreatic carcinogenesis, i.e. ADM models and established PDAC. In addition, we analyzed the expression of KIAA1967, a key mediator of Sirt1 function, along with potential Sirt1 downstream targets. Sirt1 was co-expressed with KIAA1967 in the nuclei of normal pancreatic acinar cells. In ADM, Sirt1 underwent a transient nuclear-tocytoplasmic shuttling. Experiments where during ADM, we enforced repression of Sirt1 shuttling, inhibition of Sirt1 activity or modulation of its expression, all underscore that the temporary decrease of nuclear and increase of cytoplasmic Sirt1 stimulate ADM. Our results further underscore that important transcriptional regulators of acinar differentiation, that is, Pancreatic transcription factor-1a and b-catenin can be deacetylated by Sirt1. Inhibition of Sirt1 is effective in suppression of ADM and in reducing cell viability in established PDAC tumors. KIAA1967 expression is differentially downregulated in PDAC and impacts on the sensitivity of PDAC cells to the Sirt1/2 inhibitor Tenovin-6. In PDAC, acetylation of b-catenin is not affected, unlike p53, a well-characterized Sirt1-regulated protein in tumor cells. Our results reveal that Sirt1 is an important regulator and potential therapeutic target in pancreatic carcinogenesis. Cancer Res; 73(7); 2357-67. Ó2012 AACR.

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“…CD133 is not expressed in most postnatal and adult epithelia [4], but it is present in adult pancreatic ducts of mice and humans [6][7][8]. Although CD133 is expressed on the cell surface of adult human pancreatic ductal trees [8][9][10], some ductal cells express CD133 in the cytoplasm [10]. This has led to the speculation that adult human CD133 + duct cells may not be progenitor cells [8,10].…”

mentioning

confidence: 99%

In Vitro Multilineage Differentiation and Self-Renewal of Single Pancreatic Colony-Forming Cells from Adult C57Bl/6 Mice

Jin

Feng

Zerda

et al. 2014

Stem Cells and Development

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In a previous study we established colony assays suitable for studying murine adult (2-4 months) pancreatic progenitor cells plated in semisolid media containing methylcellulose and extracellular matrix proteins. Using these assays, we found robust in vitro progenitor cell activities (multilineage differentiation and self-renewal) from pancreatic cells of adult mice in the CD-1 outbred background. However, it was not clear whether progenitor cell activities can be detected from inbred mice, a preferred mouse model for various genetic studies. It was also not clear whether a single cell is sufficient to self-renew. Here, we show that fluorescent activated cell sorting pancreatic CD133+ but not CD133 -cells from adult C57Bl/6 inbred mice are enriched for progenitor cells that self-renew and give rise to multilineage colonies in vitro. The number of cells in a colony is in proportion to its diameter. Around 60% of single handpicked 3-week-old colonies express trilineage markers, indicating most progenitors are tripotent for ductal, acinar, and endocrine lineage differentiation. Approximately 80% of primary (freshly sorted) colony-forming progenitor cells are capable of giving rise to secondary progenitors in vitro, indicating that a majority of the primary progenitors self-renew. A single cell is sufficient for self-renewal and a Wnt agonist, R-Spondin1, enhances the number of secondary progenitors from the primary progenitors. Together, our pancreatic colony assays allow quantitative analyses of progenitors at a single-cell level from inbred mice. These assays will be useful for elucidating in vitro mechanisms of pancreatic progenitor cell biology.

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Lineage Tracing Evidence for Transdifferentiation of Acinar to Duct Cells and Plasticity of Human Pancreas

Cited by 123 publications

References 39 publications

Pancreatic ductal cells in development, regeneration, and neoplasia

Pancreatic ductal cells in development, regeneration, and neoplasia

Sirtuin-1 Regulates Acinar-to-Ductal Metaplasia and Supports Cancer Cell Viability in Pancreatic Cancer

In Vitro Multilineage Differentiation and Self-Renewal of Single Pancreatic Colony-Forming Cells from Adult C57Bl/6 Mice

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