Molecular regulation of pancreatic β-cell mass development, maintenance, and expansion

Ackermann, Amanda M.; Gannon, Maureen

doi:10.1677/jme-06-0053

Cited by 236 publications

(208 citation statements)

References 126 publications

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“…PDX-1 and insulin co-expression significantly increased by the late stage, while no colocalisation of PDX-1 and glucagon was ever observed, indicating that inactivation of PDX-1 in islet progenitors may be involved in alpha cell differentiation. These results are in agreement with previous studies on the mouse pancreas [17,25] and support the concept that PDX-1 expression is critical for specifying beta cell fate and maintaining its phenotype. Using microarray and qRT-PCR assays, we analysed the gene expression patterns of transcription factors known to be involved in rodent pancreatic development [16,17].…”

Section: Discussionsupporting

confidence: 93%

Transcription factor expression in the developing human fetal endocrine pancreas

et al. 2008

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Aims/hypothesis Morphological changes that occur during pancreatic endocrine cell differentiation have been shown in rodent systems to be dependent on sequential alterations in transcription factor expression. However, similar data for humans have been limited. The aim of the present study was to provide a connection between pancreatic morphology, transcription factor gene expression and protein localisation during human fetal development. Methods Human fetal pancreases were examined at early (8-12 weeks of fetal age), middle (14-16 weeks) and late (19-21 weeks) stages, using immunohistological, microarray and qRT-PCR analyses. Results We observed a significant decrease in pancreatic duodenal homeobox 1 (PDX-1) + /cytokeratin 19 + cells (p<0.001), with a simultaneous increase in PDX-1 + /insulin + cells from 8 to 21 weeks (p<0.05). Increased PDX-1/ insulin co-localisation within islet clusters was noted, while no co-expression of PDX-1 with glucagon was found, suggesting that loss of PDX-1 is essential for alpha cell formation. Given that neurogenin 3 (NGN3) expression is critical for establishing the endocrine cell programme in the rodent pancreas, we examined its expression pattern and colocalisation in PDX-1 + , insulin + and glucagon + cells. Colocalisation of NGN3 with PDX-1, insulin and glucagon was noted during early development, with significant decreases in middle and late stages (p<0.001). Our microarray and co-localisation analyses of transcription factors linked to NGN3 demonstrated that ISL1 transcription factor (ISL1), neurogenic differentiation 1 (NEUROD1), NK2 related transcription factor related, locus 2 (NKX2-2) and paired box gene 6 (PAX6) were upregulated during development and present in all four endocrine cell types, while NK6 related transcription factor related, locus 1 (NKX6-1) was expressed exclusively in beta cells. Conclusions/interpretation This study is an important step towards identifying key molecular factors involved in development of the human fetal endocrine pancreas.

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Section: Discussionsupporting

confidence: 93%

Transcription factor expression in the developing human fetal endocrine pancreas

et al. 2008

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“…Studies in genetic mouse models indicate the different regulators determine embryonic vs postnatal beta cell proliferation [24]. For example, D and E cyclin-cyclin-dependent kinase (CDK) complexes regulated by CDK inhibitors, including p27 kip1 and p16 cip1 , play a critical role in progression of the cell cycle from G1 to S phase in the postnatal period [7].…”

Section: Prenatal and Neonatal Periodmentioning

confidence: 99%

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Mezza

Kulkarni

2014

Diabetologia

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Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and agedependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes.

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“…There is a shorter refractory period for b-cell proliferation observed in the first four weeks postnatally and a longer refractory period after weaning (Bouwens and Rooman, 2005;Teta et al, 2007;Salpeter et al, 2010). Studies on postnatal b-cell growth and proliferation have been reviewed extensively elsewhere and will not be covered in this review (reviewed in Ackermann and Gannon, 2007;Bonner-Weir et al, 2010). In order to compensate for body growth, acinar differentiation, maturation, and proliferation also continue after birth before gradually decreasing until weaning (Desai et al, 2007;Salpeter et al, 2010).…”

mentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

514

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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Molecular regulation of pancreatic β-cell mass development, maintenance, and expansion

Cited by 236 publications

References 126 publications

Transcription factor expression in the developing human fetal endocrine pancreas

Transcription factor expression in the developing human fetal endocrine pancreas

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Pancreas organogenesis: From bud to plexus to gland

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