Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

Bogdani, Marika; Lefebvre, V.; Buelens, Nicole; Bock, Troels; Pipeleers-Marichal, M.; Veld, Peter In’t; Pipeleers, Daniël

doi:10.1007/s00125-003-1118-4

Cited by 47 publications

(42 citation statements)

References 45 publications

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“…Indeed, when grafted under the mouse kidney capsule, duct cellenriched fractions of the human pancreas generated Human pancreatic duct cell proliferation C Rescan et al beta cells only when isolated from donors less than 10 years of age. 29 Furthermore, age-related differences in membrane receptor complexes involved in signal transduction have been described. 30,31 Duct cells used in the present study were from donors aged 44 þ 11 years and thus likely to be less sensitive to extracellular signals for proliferation or/and differentiation.…”

Section: Discussionmentioning

confidence: 99%

EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade

Rescan

Bras

Lefebvre

et al. 2005

Laboratory Investigation

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Human postnatal pancreatic duct cells are a potential source of new beta cells. Factors regulating proliferation of human pancreatic duct cells in vitro are unknown. In several other cell types, this process is influenced by ligands of the ErbB receptor family. The expression and functionality of the ErbB family members and their possible role in duct cell proliferation were determined. In cultured adult human pancreatic duct cells the different members of the ErbB family (ErbB1-4) were present at transcript and protein level. Stimulation of the duct cells with epidermal growth factor (EGF) and betacellulin results in Tyr-phosphorylation of ErbB1 and ErbB2, followed by activation of Shc, MEK1/2 and ERK1/2. Duct cells with activated ErbB signaling changed morphology and motility. EGF induced proliferation of a fraction of the duct cells and treatment with PD98059 prevented Ki67 expression in EGF-supplemented cells. When transduced with recombinant adenovirus expressing constitutively activated MEK1, duct cells proliferate and spread even in the absence of EGF. Importantly, the adult human duct cells retain their capacity to recapitulate ngn3-induced embryonic (neuro)endocrine differentiation after proliferation. Therefore, the present data support a possible role for human adult pancreatic duct cells, following expansion and transdifferentiation, as a source of insulin by transplantation to type I diabetes patients.

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Section: Discussionmentioning

confidence: 99%

EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade

Rescan

Bras

Lefebvre

et al. 2005

Laboratory Investigation

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“…There is suggestive evidence that pancreatic ducts are potential sites for beta cell neogenesis [1,2,3,4,5,6,7]. Duct cells were also shown to produce nitric oxide [4] and to express MHC class II [3], leading to proposals that they might contribute to beta cell damage in Type 1 diabetes mellitus [8].…”

Section: Introductionmentioning

confidence: 99%

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

Vosters

Beuneu

Nagy³

et al. 2004

Diabetologia

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Aims/hypothesis. Human pancreatic duct cells are closely associated with islet beta cells, and contaminate islet suspensions transplanted in Type 1 diabetes mellitus patients. Activated duct cells produce cytotoxic mediators and possibly contribute to the pathogenesis of Type 1 diabetes mellitus or islet graft rejection. As CD40 transduces activation signals involved in inflammatory and immune disorders, we investigated CD40 expression on duct cells and their response to CD40 engagement. Methods. CD40 expression on human pancreatic duct cells was analysed by flow cytometry and immunohistochemical analyses. To assess the function of CD40 expression on duct cells, activation of the transcription factor nuclear factor-kappa B was determined using electrophoretic mobility shift assay and ELISA. Cytokine mRNA levels were quantified by real-time RT-PCR, and protein levels by Luminex technology. Results. Isolated human pancreatic duct cells and Capan-2 cell lines were found to express constitutively CD40. The expression of CD40 on duct cells was confirmed in vivo on human normal and pathological pancreatic specimens. CD40 ligation on Capan-2 cells induced rapid nuclear factor-kappa B activation, and supershift assays demonstrated that p50/p65 heterodimers and p50/p50 homodimers were present in the activated complexes in the nucleus. This activation was accompanied by tumour necrosis factor-α and interleukin-1β mRNA accumulation. Tumour necrosis factor-α protein secretion was confirmed in CD40-activated Capan-2 cells and in isolated human pancreatic duct cells. Conclusions/interpretation. Interaction between activated T lymphocytes expressing CD40 ligand and duct cells expressing CD40 may contribute to the immune responses involved in Type 1 diabetes mellitus and islet graft rejection. Interfering with CD40-mediated duct cell activation could alleviate beta cell damage of immune origin.

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“…However, many studies show that there are obvious differences between species in the capacity of beta cells to replicate. Proliferation of human beta cells in vivo appears to be extremely low at all ages [2,6,22], and this is true also for isolated islets even after transplantation to nude mice [3,7,23]. However, when placed in suitable culture conditions, human beta cells may transiently proliferate but this is invariably associated with loss of differentiated function, at least in monolayer cultures [15,24].…”

Section: Discussionmentioning

confidence: 99%

“…Morphological observations also suggest the appearance of neogenic islet cells with ductal origin in the human pancreas [6]. There is direct evidence of islet cell differentiation from experimentally transplanted human ductal cells taken from young donors [7]. Furthermore, a recent analysis of the cellular composition of clinical islet grafts shows that longterm graft function correlates with the number of transplanted ductal cells [8].…”

Section: Introductionmentioning

confidence: 97%

In vitro neogenesis of human islets reflects the plasticity of differentiated human pancreatic cells

et al. 2005

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Aims/hypothesis: The neogenesis of islets from cultured human adult pancreatic tissue has been reported. The islet progenitors have been thought to be ductal cells. Since previous experiments have been 'contaminated' by a number of pre-existing islet cells, we examined their involvement in islet cell neogenesis. Methods: Fresh human pancreatic cells with different purities of islet cells were grown in monolayer culture and labelled with bromodeoxyuridine. Transitional cells were analysed by double immunofluorescence staining. For purified ductal cell culture, pre-existing islets were eliminated on a magnetic cell separation system. Results: We confirmed that less than 1% of the endocrine cells proliferated, mainly during the first 48 h of culture. However, a 10-fold larger proportion of the cells acquired a transitional phenotype by starting to coexpress the ductal marker cytokeratin 19 (CK19). These cells represented more than 10% of all endocrine cells after 1 day in culture, and 6% at 5 days of culture. Using magnetic cell sorting, we eliminated cells expressing neural cell adhesion molecule (N-CAM), after which we obtained 99.7% pure non-endocrine CK19-rich cell populations. These cell populations could be expanded in vitro. However, their endocrine differentiation capacity was severely reduced as compared with the original mixed cell cultures. Conclusions/interpretation: These results suggest that islet neogenesis in this culture system at least partly represents the de-differentiation of islet cells into a ductcell-like phenotype, with further re-differentiation in appropriate conditions. The plasticity of differentiated human pancreatic cell types may thus be an important mechanism of human pancreas regeneration.

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Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

Cited by 47 publications

References 45 publications

EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade

EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

In vitro neogenesis of human islets reflects the plasticity of differentiated human pancreatic cells

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