Ectopic expression of <i>Pax4</i> in pancreatic δ cells results in β-like cell neogenesis

Druelle, Noémie; Vieira, Andhira; Shabro, Aidin; Courtney, Monica; Mondin, Magali; Rekima, Samah; Napolitano, Tiziana; Silvano, Serena; Navarro-Sanz, Sergi; Hadzić, B; Avolio, Fabio; Rassoulzadegan, Minoo; Schmid, Herbert; Mansouri, Ahmed; Collombat, Patrick

doi:10.1083/jcb.201704044

Cited by 28 publications

(33 citation statements)

References 22 publications

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“…An origin of endocrine cells from ductal epithelium was suggested several years ago (44) and reported in a case of partial pancreatectomy (45). Although the significantly reduced percentage of α and δ cells ( Figure 1G) suggests that these islet cell types are a source of β cell neogenesis as reported recently (43,46), additional lineage-tracing studies are necessary to confirm this possibility. Our previous studies also suggest an association between insulin resistance and increased islet neogenesis in pancreas sections from insulin-resistant humans (47).…”

Section: Discussionmentioning

confidence: 51%

Human duct cells contribute to β cell compensation in insulin resistance

Dirice¹,

Jesus²,

Kahraman³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 51%

Human duct cells contribute to β cell compensation in insulin resistance

Dirice¹,

Jesus²,

Kahraman³

et al. 2019

JCI Insight

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“…To test this possibility, we transcriptionally profiled BON and QGP cells using a battery of genes involved in pancreatic, pancreatic endocrine, and islet cell differentiation. PAX4 which is crucial for βand δ-cell development, β/δ-cell lineage bifurcation, and conversion of αor δ-cells into functional β-like cells [16] is restricted at later stages to β-cells. We found that the transcript levels for PAX4 are 10-20-fold more abundant in NT-3 cells than in the two permanent cell lines ( Figure 4A).…”

Section: Expression Of Genes Of Immature β-Cells and Lineage-specificmentioning

confidence: 99%

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

Luley

Biedermann

Künstner

et al. 2020

Cancers

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Experimental models of neuroendocrine tumor disease are scarce, with only a few existing neuroendocrine tumor cell lines of pancreatic origin (panNET). Their molecular characterization has so far focused on the neuroendocrine phenotype and cancer-related mutations, while a transcription-based assessment of their developmental origin and malignant potential is lacking. In this study, we performed immunoblotting and qPCR analysis of neuroendocrine, epithelial, developmental endocrine-related genes as well as next-generation sequencing (NGS) analysis of microRNAs (miRs) on three panNET cell lines, BON-1, QGP-1, and NT-3. All three lines displayed a neuroendocrine and epithelial phenotype; however, while insulinoma-derived NT-3 cells preferentially expressed markers of mature functional pancreatic β-cells (i.e., INS, MAFA), both BON-1 and QGP-1 displayed high expression of genes associated with immature or non-functional β/δ-cells genes (i.e., NEUROG3), or pancreatic endocrine progenitors (i.e., FOXA2). NGS-based identification of miRs in BON-1 and QGP-1 cells revealed the presence of all six members of the miR-17-92 cluster, which have been implicated in β-cell function and differentiation, but also have roles in cancer being both oncogenic or tumor suppressive. Notably, both BON-1 and QGP-1 cells expressed several miRs known to be negatively associated with epithelial-mesenchymal transition, invasion or metastasis. Moreover, both cell lines failed to exhibit migratory activity in vitro.Cancers 2020, 12, 691 2 of 18 Taken together, NT-3 cells resemble mature functional β-cells, while both BON-1 and QGP-1 are more similar to immature/non-functional pancreatic β/δ-cells or pancreatic endocrine progenitors. Based on the recent identification of three transcriptional subtypes in panNETs, NT-3 cells resemble the "islet/insulinoma tumors" (IT) subtype, while BON-1 and QGP-1 cells were tentatively classified as "metastasis-like/primary" (MLP). Our results provide a comprehensive characterization of three panNET cell lines and demonstrate their relevance as neuroendocrine tumor models.

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“…It also promotes pancreatic cell lineage. All these findings therefore allow us to conclude that the expression of PAX4 in somatostatin-positive cells promotes their differentiation into β-like cells, apparently through Hhex down-regulation [145].…”

Section: Ectopic Expression Of Pax4mentioning

confidence: 67%

“…It was shown that PAX4 ectopic expression is sufficient for the conversion of δ-cells into functional insulin-producing cells. Mostly, these induced insulin-producing cells were functional and could slightly change the consequences of chemically-induced diabetes [145]. The ectopic expression of PAX4, either in PDX1-positive or PAX6-positive endocrine cells, led to the observation of β-cell characteristics.…”

Section: Ectopic Expression Of Pax4mentioning

confidence: 99%

“…The ectopic expression of PAX4, either in PDX1-positive or PAX6-positive endocrine cells, led to the observation of β-cell characteristics. PAX4 acts on the specification of EP cells by enhancing the pancreatic β-cell lineage [131,145]. It was shown that the specific loss of ARX and PAX4 ectopic expression in α-cells leads to the transformation of α-cells into insulin-producing cells [63,131,146].…”

Section: Ectopic Expression Of Pax4mentioning

confidence: 99%

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Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies

Thakur

Lee

Jeon

et al. 2020

IJMS

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Diabetes is a metabolic disease which affects not only glucose metabolism but also lipid and protein metabolism. It encompasses two major types: type 1 and 2 diabetes. Despite the different etiologies of type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively), the defining features of the two forms are insulin deficiency and resistance, respectively. Stem cell therapy is an efficient method for the treatment of diabetes, which can be achieved by differentiating pancreatic β-like cells. The consistent generation of glucose-responsive insulin releasing cells remains challenging. In this review article, we present basic concepts of pancreatic organogenesis, which intermittently provides a basis for engineering differentiation procedures, mainly based on the use of small molecules. Small molecules are more auspicious than any other growth factors, as they have unique, valuable properties like cell-permeability, as well as a nonimmunogenic nature; furthermore, they offer immense benefits in terms of generating efficient functional beta-like cells. We also summarize advances in the generation of stem cell-derived pancreatic cell lineages, especially endocrine β-like cells or islet organoids. The successful induction of stem cells depends on the quantity and quality of available stem cells and the efficient use of small molecules.

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Ectopic expression of Pax4 in pancreatic δ cells results in β-like cell neogenesis

Cited by 28 publications

References 22 publications

Human duct cells contribute to β cell compensation in insulin resistance

Human duct cells contribute to β cell compensation in insulin resistance

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

Small Molecule-Induced Pancreatic β-Like Cell Development: Mechanistic Approaches and Available Strategies

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