Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3

Blum, Barak; Hrvatin, Siniša; Schuetz, Christian; Bonal, Claire; Rezania, Alireza; Melton, Douglas A.

doi:10.1038/nbt.2141

Cited by 347 publications

(408 citation statements)

References 14 publications

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“…Ucn3 is a late maturation marker for primary and stem cell-derived beta cells (Blum et al, 2012;van der Meulen et al, 2012) that continued to increase progressively weeks after beta cell expression of Nkx6-1 and Mafa reached steady state, and coincided with the gradual loss of Mafb from beta cells ( Figure 1A) (Artner et al, 2010).…”

Section: Ucn3-negative Immature Beta Cells Persist Throughout Lifementioning

confidence: 99%

“…This is evident from the presence of a distinct population of immature beta cells at the islet periphery that does not yet express the late maturation marker Urocortin3 (Ucn3) (Blum et al, 2012;van der Meulen and Huising, 2014;van der Meulen et al, 2012). Similar Ucn3-negative beta cells are readily identifiable in human pancreas of different ages and in donors with T1D.…”

Section: Introductionmentioning

confidence: 99%

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Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

et al. 2017

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Section: Ucn3-negative Immature Beta Cells Persist Throughout Lifementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

et al. 2017

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“…By late gestation (around E18.5), the endocrine cells are loosely arranged as small clusters; at this stage bcells cannot sense glucose and secrete insulin [11,12]. Immediately after birth, b-cells undergo extensive proliferation and functional maturation [13,14]. Progenitor cells may linger in the postnatal pancreas, as suggested by lineage-tracing experiments that showed that a portion of duct cells labeled with sex-determining region box 9 (Sox9) [15] or carbonic anhydrase II could contribute to new endocrine cells [16].…”

Section: Onward Ngn3mentioning

confidence: 99%

Postnatal Pancreas of Mice Contains Tripotent Progenitors Capable of Giving Rise to Duct, Acinar, and Endocrine Cells In Vitro

Ghazalli

Mahdavi

Feng

et al. 2015

Stem Cells and Development

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Postnatal pancreas is a potential source for progenitor cells to generate endocrine b-cells for treating type 1 diabetes. However, it remains unclear whether young (1-week-old) pancreas harbors multipotent progenitors capable of differentiating into duct, acinar, and endocrine cells. Laminin is an extracellular matrix (ECM) protein important for b-cells' survival and function. We established an artificial extracellular matrix (aECM) protein that contains the functional IKVAV (Ile-Lys-Val-Ala-Val) sequence derived from laminin (designated aECM-lam). Whether IKVAV is necessary for endocrine differentiation in vitro is unknown. To answer these questions, we cultured single cells from 1-week-old pancreas in semi-solid media supplemented with aECMlam, aECM-scr (which contains a scrambled sequence instead of IKVAV), or Matrigel. We found that colonies were generated in all materials. Individual colonies were examined by microfluidic reverse transcriptionpolymerase chain reaction, immunostaining, and electron microscopy analyses. The majority of the colonies expressed markers for endocrine, acinar, and ductal lineages, demonstrating tri-lineage potential of individual colony-forming progenitors. Colonies grown in aECM-lam expressed higher levels of endocrine markers Insulin1, Insulin2, and Glucagon compared with those grown in aECM-scr and Matrigel, indicating that the IKVAV sequence enhances endocrine differentiation. In contrast, Matrigel was inhibitory for endocrine gene expression. Colonies grown in aECM-lam displayed the hallmarks of functional b-cells: mature insulin granules and glucose-stimulated insulin secretion. Colony-forming progenitors were enriched in the CD133 high fraction and among 230 micro-manipulated single CD133 high cells, four gave rise to colonies that expressed tri-lineage markers. We conclude that young postnatal pancreas contains multipotent progenitor cells and that aECM-lam promotes differentiation of b-like cells in vitro.

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“…Urocortin-3 expression has been used to identify mature, fully functional, β-cells during pancreas development 5 and is expressed at approximately equal levels in α-and β-cells in non-diabetic adult human pancreas 13 . Absence of detectable beta-cell urocortin-3 staining in all transplanted islets examined in the current study provides evidence for loss of end-differentiated phenotype despite maintained insulin expression and near-normoglycemia.…”

Section: Discussionmentioning

confidence: 99%

“…This is in contrast to vascularised whole pancreas transplant where normalisation of β-cell secretory capacity has been confirmed 4 . During pancreas development co-expression of insulin and the peptide hormone urocortin-3 is a phenotypic marker of full β-cell maturation 5 . Maintenance of β-cell urocortin-3 expression is required for physiological regulation of insulin secretion, with urocortin-3 null mice having deficient insulin secretion during periods of high glucose 6 .…”

Section: Introductionmentioning

confidence: 99%

Loss of end-differentiated β-cell phenotype following pancreatic islet transplantation

Anderson

White

Armour

et al. 2018

American Journal of Transplantation

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Replacement of pancreatic -cells through deceased donor islet transplantation is a proven therapy for preventing recurrent life-threatening hypoglycemia in type 1 diabetes. Although near-normal glucose levels and insulin independence can be maintained for many years following successful islet transplantation, restoration of normal functional -cell mass has remained elusive. It has recently Accepted ArticleThis article is protected by copyright. All rights reserved.been proposed that dedifferentiation / plasticity towards other endocrine phenotypes may play an important role in stress-induced -cell dysfunction in type 2 diabetes. Here we report loss of enddifferentiated -cell phenotype in two intraportal islet allotransplant recipients. Despite excellent graft function and sustained insulin independence, all examined insulin-positive cells had lost expression of the end-differentiation marker, urocortin-3, or appeared to co-express the α-cell marker, glucagon. In contrast, no insulin + / urocortin-3 -cells were seen in non-diabetic deceased donor control pancreatic islets. Loss of end-differentiated phenotype may facilitate β-cell survival during the stresses associated with islet isolation and culture, in addition to sustained hypoxia following engraftment. As further refinements in islet isolation and culture are made in parallel with exploration of alternative β-cell sources, graft sites and ultimately fully-vascularised bioengineered insulin-secreting microtissues, differentiation status immunostaining provides a novel tool to assess whether fully mature β-cell phenotype has been maintained.

show abstract

Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3

Cited by 347 publications

References 14 publications

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

Postnatal Pancreas of Mice Contains Tripotent Progenitors Capable of Giving Rise to Duct, Acinar, and Endocrine Cells In Vitro

Loss of end-differentiated β-cell phenotype following pancreatic islet transplantation

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