Pax4 acts as a key player in pancreas development and plasticity

Napolitano, Tiziana; Avolio, Fabio; Courtney, Monica; Vieira, Andhira; Druelle, Noémie; Ben-Othman, Nouha; Hadzić, B; Navarro, Sergi; Collombat, Patrick

doi:10.1016/j.semcdb.2015.08.013

Cited by 58 publications

(53 citation statements)

References 83 publications

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“…PAX4 is mainly expressed in the endocrine pancreas where it plays an essential role in the generation of insulin producing β-cells during embryonic development and later on, during adulthood, is a β-cell master regulator in adaptation processes [10,17,18,19]. …”

Section: Pax4 In Islet Physiology: Key Player In β-Cell Generationmentioning

confidence: 99%

The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

Lorenzo

Juárez-Vicente

Cobo-Vuilleumier

et al. 2017

Genes

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Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates β-cell proliferation and increases their resistance to apoptosis. Additionally, in an experimental model of autoimmune diabetes, a novel immunomodulatory function for this factor has been suggested. Altogether these data pinpoint at PAX4 as an important target for novel regenerative therapies for diabetes treatment, aiming at the preservation of the remaining β-cells in parallel to the stimulation of their proliferation to replenish the β-cell mass lost during the progression of the disease. However, the adequate development of such therapies requires the knowledge of the molecular mechanisms controlling the expression of PAX4 as well as the downstream effectors that could account for PAX4 action.

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Section: Pax4 In Islet Physiology: Key Player In β-Cell Generationmentioning

confidence: 99%

The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

Lorenzo

Juárez-Vicente

Cobo-Vuilleumier

et al. 2017

Genes

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“…Because of potential implications of gastrin in β-cell mass regeneration in rodents [Suarez-Pinzon et al 2008;Suissa et al 2013], a recent study evaluated the role of gastrin in promoting β-cell neogenesis from ductal cells in 90% Px rats [Tellez and Montanya, 2014]. In the gastrin-treated mice, strong proliferation activity was Xu et al [2006] In vivo Treatment with exendin-4 facilitated β-cell neogenesis in pancreatic ducts Tokui et al [2006] In vivo Betacellulin promoted ductal differentiation towards insulin-expressing cells Inada et al [2008] In vivo β-cell mass replenishment occurred from ductal cells 2 weeks post PDL Bonner-Weir et al [2008] In vivo Partial pancreatic tissue regeneration occurred from ductal cells Xu et al [2008] In vivo Re-expression of NGN3 in ductal lining cells occurred 1 week after PDL Criscimanna et al [2011] In vivo Proliferative ducts expressed acinar and endocrine markers 3/4 weeks post-DT injection Wang et al [2012] In vivo Administration of gastrin and EGF increased β-cell neogenesis Pfeifer et al [2013] In vivo Requirement of EMT for duct-lining cells differentiation into endocrine cells In vivo Continuous activation of NGN3 + cells along the lining duct occurred after ARX inhibition Téllez et al [2014] In vivo Appearance of β-cell clusters from ductal epithelium occurred 3 days post 90% Px Lemaire et al [2015] In vivo Bicaudal C1 expressed in duct lining cells was essential for progenitor differentiation Yamaguchi et al [2015] In vivo Pancreatic ductal glands contained niches of progenitor cells Carpino et al [2015] In vivo Pancreatic ductal glands as container of niches for pancreatic precursors Napolitano et al [2015] In vivo Continuous activation of NGN3 + cells along the lining duct occurred after PAX4 overexpression El-Gohary et al [2016] In vivo Duct-to-β-cell conversion occurred after partial Px in mice overexpressing TGF-β receptor Zhang et al [2016] In vivo Conversion of SOX9 + cells into insulin-producing cells occurred after administration of gastrin and EGF Seaberg et al [2004] In vitro Progenitor colonies arose from islet and ducts cultured with EGF and FGF2 Rovira et al [2010] In vitro Centroacinar/terminal ductal cells with progenitor-like phenotype ARX, aristaless related homeobox; DT, diphtheria toxin; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; PDL, pancreatic duct ligation; Px, pancreatectomy; TGF, transforming growth factor.…”

Section: In Vivo Studies On Pancreatic Progenitorsmentioning

confidence: 99%

β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells

Corritore

Lee

Sokal

et al. 2016

Therapeutic Advances in Endocrinology

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Thorough research on the capacity of human islet transplantation to cure type 1 diabetes led to the achievement of 3-to 5-year-long insulin independence in nearly half of transplanted patients. Yet, translation of this technique to clinical routine is limited by organ shortage and the need for long-term immunosuppression, restricting its use to adults with unstable disease. The production of new bona fide β cells in vitro was thus investigated and finally achieved with human pluripotent stem cells (PSCs). Besides ethical concerns about the use of human embryos, studies are now evaluating the possibility of circumventing the spontaneous tumor formation associated with transplantation of PSCs. These issues fueled the search for cell candidates for β-cell engineering with safe profiles for clinical translation. In vivo studies revealed the regeneration capacity of the exocrine pancreas after injury that depends at least partially on facultative progenitors in the ductal compartment. These stimulated subpopulations of pancreatic ductal cells (PDCs) underwent β-cell transdifferentiation through reactivation of embryonic signaling pathways. In vitro models for expansion and differentiation of purified PDCs toward insulin-producing cells were described using cocktails of growth factors, extracellular-matrix proteins and transcription factor overexpression. In this review, we will describe the latest findings in pancreatic β-cell mass regeneration due to adult ductal progenitor cells. We will further describe recent advances in human PDC transdifferentiation to insulin-producing cells with potential for clinical translational studies.

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“…Notably, the expression of the Arx gene has been shown to be crucial in promoting islet progenitors towards the α and PP cell lineages (Collombat et al 2007), as its inhibition induced by the Pax gene is required to form β and δ cells (Napolitano et al 2015). It is totally unknown whether the location of δ and PP cells in islets is also dictated by differential expressions of these or other genes.…”

Section: Discussionmentioning

confidence: 99%

Asymmetrical distribution of δ and PP cells in human pancreatic islets

Barbieux

Parnaud

Lavallard

et al. 2016

Journal of Endocrinology

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The aim of this study was to evaluate the location of PP and δ cells in relation to the vascularization within human pancreatic islets. To this end, pancreas sections were analysed by immunofluorescence using antibodies against endocrine islet and endothelial cells. Staining in different islet areas corresponding to islet cells adjacent or not to peripheral or central vascular channels was quantified by computerized morphometry. As results, α, PP and δ cells were preferentially found adjacent to vessels. In contrast to α cells, which were evenly distributed between islet periphery and intraislet vascular channels, PP and δ cells had asymmetric and opposite distributions: PP staining was higher and somatostatin staining was lower in the islet periphery than in the area around intraislet vascular channels. Additionally, frequencies of PP and δ cells were negatively correlated in the islets. No difference was observed between islets from the head and the tail of the pancreas, and from type 2 diabetic and non-diabetic donors. In conclusion, the distribution of δ cells differs from that of PP cells in human islets, suggesting that vessels at the periphery and at the centre of islets drain different hormonal cocktails.

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Pax4 acts as a key player in pancreas development and plasticity

Cited by 58 publications

References 83 publications

The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences

β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells

Asymmetrical distribution of δ and PP cells in human pancreatic islets

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