Cellular and molecular mechanisms coordinating pancreas development

Bastidas-Ponce, Aimée; Scheibner, Katharina; Lickert, Heiko; Bakhti, Mostafa

doi:10.1242/dev.140756

Cited by 146 publications

(164 citation statements)

References 238 publications

(282 reference statements)

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“…Both protocols activated Activin/TGFb, FGF, RA, and PKC while inhibited GSK3b, SHH, and BMP signaling pathways (Pagliuca et al, 2014). In current study, we used a 10-day adherent culture that (Attali et al, 2007;Bastidas-Ponce et al, 2017;Landsman et al, 2011). Through the next steps of lineage determination, these endocrine clusters are penetrated by a dense network of EC which is critical for morphogenesis and development of the pancreas (Guney & Gannon, 2009).…”

Section: Formation Of Po By Integrating Multiple Derivatives Of Hummentioning

confidence: 99%

Generation of functional human pancreatic organoids by transplants of embryonic stem cell derivatives in a 3D‐printed tissue trapper

Soltanian

Ghezelayagh

Mazidi

et al. 2018

Journal Cellular Physiology

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Organoids can be regarded as a beneficial tool for discovery of new therapeutics for diabetes and/or maturation of pancreatic progenitors (PP) towards β cells. Here, we devised a strategy to enhance maturation of PP by assembly of three‐dimensional (3D) pancreatic organoids (PO) containing human embryonic stem (ES) cell derivatives including ES‐derived pancreatic duodenal homeobox 1 (PDX1) + early PP, mesenchymal stem cells, and endothelial cells at an optimized cell ratio, on Matrigel. The PO was placed in a 3D‐printed tissue trapper and heterotopically implanted into the peritoneal cavity of immunodeficient mice where it remained for 90 days. Our results indicated that, in contrast to corresponding early PP transplants, 3D PO developed more vascularization as indicated by greater area and number of vessels, a higher number of insulin‐positive cells and improvement of human C‐peptide secretions. Based on our findings, PO‐derived β cells could be considered a novel strategy to study human β‐cell development, novel therapeutics, and regenerative medicine for diabetes.

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Section: Formation Of Po By Integrating Multiple Derivatives Of Hummentioning

confidence: 99%

Generation of functional human pancreatic organoids by transplants of embryonic stem cell derivatives in a 3D‐printed tissue trapper

Soltanian

Ghezelayagh

Mazidi

et al. 2018

Journal Cellular Physiology

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“…During embryogenesis, all pancreatic lineages arise from multipotent progenitor (MP) cells. The developmental potential of these progenitors is restricted in a stepwise manner, ultimately resulting in the generation of the exocrine and islet endocrine lineages (Pan & Wright, ; Shih et al , ; Bastidas‐Ponce et al , ; Larsen & Grapin‐Botton, ). In mice, the pancreatic anlagen is detected in a dorsal definitive endoderm domain as early as embryonic day 8.5 (E8.5) and in a ventral endoderm domain approximately half a day later (Gittes, ).…”

Section: Introductionmentioning

confidence: 99%

Defining multistep cell fate decision pathways during pancreatic development at single‐cell resolution

Qiu

Liu

et al. 2019

The EMBO Journal

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The generation of terminally differentiated cell lineages during organogenesis requires multiple, coordinated cell fate choice steps. However, this process has not been clearly delineated, especially in complex solid organs such as the pancreas. Here, we performed single‐cell RNA‐sequencing in pancreatic cells sorted from multiple genetically modified reporter mouse strains at embryonic stages E9.5–E17.5. We deciphered the developmental trajectories and regulatory strategies of the exocrine and endocrine pancreatic lineages as well as intermediate progenitor populations along the developmental pathways. Notably, we discovered previously undefined programs representing the earliest events in islet α‐ and β‐cell lineage allocation as well as the developmental pathway of the “first wave” of α‐cell generation. Furthermore, we demonstrated that repressing ERK pathway activity is essential for inducing both α‐ and β‐lineage differentiation. This study provides key insights into the regulatory mechanisms underlying cell fate choice and stepwise cell fate commitment and can be used as a resource to guide the induction of functional islet lineage cells from stem cells in vitro.

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“…Although deterministic cues and stochastic gene expression are known to govern cell-type specification in neurogenesis and retinogenesis (Doe, 2017; Wang and Cepko, 2016), the mechanisms regulating cell specification in most other organs remain poorly understood. These include the pancreatic endocrine islets, which comprise four major cell types – the α, β, δ, and γ cells that secrete glucagon (Gcg), insulin (Ins), somatostatin (Sst), pancreatic polypeptide (Ppy), respectively, and a minor ε cell type that secrete ghrelin (Ghrl) (Bastidas-Ponce et al, 2017; Jennings et al, 2015; Larsen and Grapin-Botton, 2017; Romer and Sussel, 2015). …”

Section: Introductionmentioning

confidence: 99%

Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity

et al. 2019

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Summary In the developing pancreas, transient Neurog3-expressing progenitors give rise to four major islet-cell types, α, β, δ, and γ; when and how the Neurog3+ cells choose cell-fate is unknown. Using single-cell RNAseq, trajectory analysis, and combinatorial lineage tracing, we showed here that the Neurog3+ cells co-expressing Myt1 (i.e., Myt1+Neurog3+) were biased towards β-cell fate; while those not simultaneously expressing Myt1 (Myt1-Neurog3+) favored α-fate. Myt1 manipulation only marginally affected α- vs. β-cell specification, suggesting Myt1 as a marker but not determinant for islet-cell type specification. The Myt1+Neurog3+ cells displayed higher Dnmt1 expression and enhancer methylation at Arx, an α-fate-promoting gene. Inhibiting Dnmts in pancreatic progenitors promoted α-cell specification, while Dnmt1 over-expression or Arx enhancer hyper-methylation favored β-cell production. Moreover, the pancreatic progenitors contained distinct Arx enhancer methylation states without transcriptionally definable sub-populations, a phenotype independent of Neurog3 activity. These data suggest that Neurog3-independent methylation on fate-determining gene-enhancers specifies distinct endocrine-cell programs.

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Cellular and molecular mechanisms coordinating pancreas development

Cited by 146 publications

References 238 publications

Generation of functional human pancreatic organoids by transplants of embryonic stem cell derivatives in a 3D‐printed tissue trapper

Generation of functional human pancreatic organoids by transplants of embryonic stem cell derivatives in a 3D‐printed tissue trapper

Defining multistep cell fate decision pathways during pancreatic development at single‐cell resolution

Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity

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