Plasticity in the adult rat pancreas: Transdifferentiation of exocrine to hepatocyte-like cells in primary culture

Lardon, Jessy; Breuck, S. De; Rooman, Ilse; Lommel, Leentje Van; Kruhøffer, Mogens; Ørntoft, Torben F.; Schuit, Frans; Bouwens, Luc

doi:10.1002/hep.20213

Cited by 75 publications

(63 citation statements)

References 45 publications

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“…It has also been demonstrated that the acinar exocrine cell line AR42J can transdifferentiate in vitro into the beta cell phenotype [31] or into hepatocytes [32]. We recently found that normal acinar cells can transdifferentiate into hepatocytes [15] and in the present study we provide evidence for a transdifferentiation into beta cells. Very recently, a "spontaneous" transdifferentiation of acinar to insulin-expressing cells has also been reported by others in a primary culture model [33].…”

Section: Discussionsupporting

confidence: 79%

“…In the presence of dexamethasone, we showed that these cells can transdifferentiate into hepatocyte-like cells [15]. For the present Fig.…”

Section: Discussionsupporting

confidence: 61%

“…We have shown that differentiated exocrine cells can revert to a partially dedifferentiated state with the capacity to transdifferentiate into different phenotypes, including ductal cells [13,14], hepatocyte-like cells [15] and insulinpositive cells [16]. This suggests that exocrine cells, which represent the great majority of cells in this organ, can be used to generate endocrine cells under the appropriate conditions.…”

Section: Introductionmentioning

confidence: 98%

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In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

Baeyens¹,

Breuck²,

Lardon³

et al. 2004

Diabetologia

291

224

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Aims/hypothesis: Transplantation of insulinproducing beta cells from donors can cure diabetes, but they are available in insufficient quantities. In this study, we investigated the possibility of generating insulinproducing cells from adult rat exocrine cells cultured in the presence of growth factors. Methods: Rat exocrine pancreatic cells were isolated and treated in vitro with epidermal growth factor (EGF) and leukaemia inhibitory factor (LIF). Analysis was performed by immunocytochemistry, DNA measurement and radioimmunoassay. Cells were transplanted to alloxan-treated (70 mg/kg) nude mice and glycaemia was monitored for 21 days. Nephrectomy was performed on day 15. Results: In a 3-day culture period, addition of LIF plus EGF to the medium resulted in an 11-fold increase of the beta cell mass. This could not be attributed to the very low mitotic activity of contaminating beta cells. Furthermore, when contaminating beta cells were initially destroyed with alloxan, this effect was even more pronounced. The newly formed cells secreted insulin in response to glucose and were immunoreactive for C-peptide-I, Pdx-1 and GLUT-2, which are characteristics of mature beta cells. Electron microscopy showed that they also contained insulinimmunoreactive secretory granules. Some insulin-positive cells were immunoreactive for amylase and cytokeratin-20, or were binucleated, which are characteristics of exocrine cells. The cells were able to restore normoglycaemia when transplanted to alloxan-diabetic mice, and hyperglycaemia recurred upon removal of the graft. Conclusions/interpretation: Our study shows that functional beta cells can be generated from exocrine tissue by transdifferentiation and thereby may offer a new perspective for beta cell therapy.

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Section: Discussionsupporting

confidence: 79%

“…In the presence of dexamethasone, we showed that these cells can transdifferentiate into hepatocyte-like cells [15]. For the present Fig.…”

Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

Baeyens¹,

Breuck²,

Lardon³

et al. 2004

Diabetologia

291

224

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“…8,10 External stimuli can induce a phenotypical switch in these cells towards a hepatocyte-like phenotype. 7 We have recently developed a model for in vitro beta-cell neogenesis based upon growth factor stimulation of dedifferentiated acinar pancreatic cells. 11 The molecular regulation of this transdifferentiation from acinar to beta cells is unknown at present.…”

Section: Introductionmentioning

confidence: 99%

“…A possible source of progenitor cells is the acinar cell population that is the most abundant in adult pancreas and is known to retain a remarkable plasticity both in vivo and in vitro. [7][8][9] Isolated acinar cells can undergo dedifferentiation in vitro whereby they lose their zymogen granules and gain a duct-like phenotype including expression of the duct cell marker cytokeratin20. 8,10 External stimuli can induce a phenotypical switch in these cells towards a hepatocyte-like phenotype.…”

Section: Introductionmentioning

confidence: 99%

Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway

Baeyens¹,

Bonné²,

German³

et al. 2006

Cell Death Differ

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The basic helix-loop-helix protein Neurogenin3 specifies precursor cells of the endocrine pancreas during embryonic development, and is thought to be absent postnatally. We have studied Ngn3 expression during in vitro generation of beta-cells from adult rat exocrine pancreas tissue treated with epidermal growth factor and leukaemia inhibitory factor. This treatment induced a transient expression of both Ngn3 and its upstream activator hepatocyte nuclear factor 6. Inhibition of EGF and LIF signalling by pharmacological antagonists of the JAK2/STAT3 pathway, or knockdown of Ngn3 by RNA interference prevented the generation of new insulin-positive cells. This study demonstrates that in vitro growth factor stimulation can induce recapitulation of an embryonic endocrine differentiation pathway in adult dedifferentiated exocrine cells. This could prove to be important for understanding the mechanism of beta-cell regeneration and for therapeutic ex vivo neogenesis of beta cells. Keywords: neurogenin3; transdifferentiation; beta cell; pancreas; diabetes Abbreviations: CK20, cytokeratin 20; EGF, epidermal growth factor; eGFP, enhanced green fluorescent protein; Hnf6, hepatocyte nuclear factor 6; JAK2, Janus kinase 2; LIF, leukaemia inhibitory factor; Ngn3, neurogenin 3; Pdx1, pancreatic and duodenal homeobox 1; STAT3, signal transducer and activator of transcription 3 IntroductionThere is currently a lot of interest in the development of a treatment for diabetes that is based on beta-cell replacement or regeneration. Beta-cells could be (re-)generated by stimulation of beta-cell replication and/or (trans-)differentiation of stem/progenitor cells. It has been demonstrated that, during adult life, beta-cell maintenance and compensatory growth in mice results primarily from proliferation of the pre-existing beta cells. 1 However, numerous reports of alternative sources of beta-cell 'neogenesis' in response to severe tissue injury have been described. [2][3][4][5][6] The pancreas is composed of exocrine tissue, comprising acinar and duct cells, and of endocrine tissue that contains beta-, alpha-, delta-and pancreatic polypeptide cells. A possible source of progenitor cells is the acinar cell population that is the most abundant in adult pancreas and is known to retain a remarkable plasticity both in vivo and in vitro. 7-9 Isolated acinar cells can undergo dedifferentiation in vitro whereby they lose their zymogen granules and gain a duct-like phenotype including expression of the duct cell marker cytokeratin20. 8,10 External stimuli can induce a phenotypical switch in these cells towards a hepatocyte-like phenotype. 7 We have recently developed a model for in vitro beta-cell neogenesis based upon growth factor stimulation of dedifferentiated acinar pancreatic cells. 11 The molecular regulation of this transdifferentiation from acinar to beta cells is unknown at present. Although it is known that during pancreatic regeneration the exocrine population can dedifferentiate towards an embryonic-like state in vivo, 12 in v...

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Overview of Stem and Artificial Cells

Soto-Gutiérrez

Navarro-Alvarez

Rivas‐Carrillo

et al. 2010

Pharmaceutical Sciences Encyclopedia

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Plasticity in the adult rat pancreas: Transdifferentiation of exocrine to hepatocyte-like cells in primary culture

Cited by 75 publications

References 45 publications

In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells

Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway

Overview of Stem and Artificial Cells

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