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

Baeyens, Luc; Breuck, S. De; Lardon, Jessy; Mfopou, Josué Kunjom; Rooman, Ilse; Bouwens, Luc

doi:10.1007/s00125-004-1606-1

Cited by 291 publications

(243 citation statements)

References 39 publications

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“…Growth factorinduced Hnf6 gene expression in cultures was markedly reduced in the presence of the inhibitor of STAT-activation Pp-YLKTK-mts (7.5-fold decrease at day 6 (Po0.01; n ¼ 3)) (Figure 1c). In the presence of nicotinamide in the medium, an agent which was shown to delay the loss of exocrine cell markers, 8,11 we found that 10-20% of all cells expressed Hnf6 in the nucleus. Sixty percent of these cells coexpressed CK20 and 45% coexpressed the acinar marker lipase (some Hnf6-positive cells expressed both CK20 and lipase) ( Figure 5).…”

Section: Growth Factor-induced Upregulation Of Hnf6mentioning

confidence: 80%

“…These observations support our hypothesis of a transdifferentiation from exocrine acinar to endocrine beta cells. 11 …”

Section: Growth Factor-induced Upregulation Of Hnf6mentioning

confidence: 99%

“…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 vitro recapitulation of the pro-endocrine developmental pathway has not yet been described at the molecular level.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Growth Factor-induced Upregulation Of Hnf6mentioning

confidence: 80%

“…These observations support our hypothesis of a transdifferentiation from exocrine acinar to endocrine beta cells. 11 …”

Section: Growth Factor-induced Upregulation Of Hnf6mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…While partial pancreatectomy in rodents rapidly induces beta cell regeneration, this process was not observed to occur in patients with pancreatic resections involving more than 50% of the initial pancreatic mass [8]. Evidence for beta cell transdifferentiation has been observed both in vitro and in vivo in animal studies [9,10], but it remains controversial as to whether this occurs in humans [11].…”

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confidence: 99%

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

et al. 2008

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Aims/hypothesis Recent histological analysis of pancreases obtained from patients with long-standing type 1 diabetes identified chronic islet inflammation and limited evidence suggestive of beta cell replication. Studies in rodent models also suggest that beta cell replication can be induced by certain inflammatory cytokines and by gastrin. We therefore tested the hypothesis that beta cell replication is observed in non-autoimmune human pancreatic disorders in which localised inflammation or elevated gastrin levels are present. Methods Resected operative pancreatic specimens were obtained from patients diagnosed with primary adenocarcinoma (with or without chronic severe pancreatitis) or gastrinoma. Additional pancreatic tissue was obtained from autopsy control patients. Immunohistochemistry was used to assess fractional insulin area, beta cell number and replication rate and differentiation factors relevant to beta cell development.Results Fractional insulin area was similar among groups. Patients with pancreatic adenocarcinoma and localised chronic severe pancreatitis displayed significant increases in the number of single beta cells, as well as increased beta cell replication rate and levels of neurogenic differentiation 1 in islets. Patients with gastrinoma demonstrated significant increases in the number of single beta cells, but the beta cell replication rate and islet differentiation factor levels were similar to those in the control group. Conclusions/interpretation These findings indicate that chronic severe pancreatic inflammation can be associated with significant effects on beta cell number or replication rate, depending on the distribution of the cells. This information may prove useful for attempts seeking to design therapies aimed at inducing beta cell replication as a means of reversing diabetes.

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“…Although stem cells were isolated from pancreatic ducts, islets and exocrine tissue the b-cell progenitors have not been identified (Baeyens et al 2005;Carlotti et al 2010;Gao et al 2003;Soria et al 2005). Interestingly, b cells mass increases in vivo significantly after injury and during metabolic demand for example pregnancy or obesity.…”

Section: Introductionmentioning

confidence: 99%

Differentiation of Stem Cells into Insulin-Producing Cells: Current Status and Challenges

Pokrywczyńska

Krzyzanowska

Jundziłł

et al. 2013

Arch. Immunol. Ther. Exp.

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Diabetes mellitus is one of the most serious public health challenges of the twenty-first century. Allogenic islet transplantation is an efficient therapy for type 1 diabetes. However, immune rejection, side effects of immunosuppressive treatment as well as lack of sufficient donor organs limits its potential. In recent years, several promising approaches for generation of new pancreatic b cells have been developed. This review provides an overview of current status of pancreatic and extra-pancreatic stem cells differentiation into insulin-producing cells and the possible application of these cells for diabetes treatment. The PubMed database was searched for English language articles published between 2001 and 2012, using the keyword combinations: diabetes mellitus, differentiation, insulin-producing cells, stem cells.

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

Cited by 291 publications

References 39 publications

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

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

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

Differentiation of Stem Cells into Insulin-Producing Cells: Current Status and Challenges

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