PDX1 Binds and Represses Hepatic Genes to Ensure Robust Pancreatic Commitment in Differentiating Human Embryonic Stem Cells

Teo, Adrian Kee Keong; Tsuneyoshi, Norihiro; Hoon, Shawn; Tan, Ee Kim; Stanton, Lawrence W.; Wright, Christopher V.E.; Dunn, N. Ray

doi:10.1016/j.stemcr.2015.02.015

Cited by 48 publications

(57 citation statements)

References 65 publications

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“…5A). Although in a slightly different cellular context, Pdx1 has been shown to be a direct effector of Nkx6.1 and Hnf6 expression (Schaffer et al, 2013;Teo et al, 2015), and as early-stage endocrine progenitors these cells are expected to express both Nkx6.1 and Hnf6. It is likely that the reduction in expression of these other factors was at least partly caused by a direct transcriptional effect because, for example, both Pdx1 and HNF6 are reported to positively control Neurog3 expression (Jacquemin et al, 2000;Oliver-Krasinski et al, 2009).…”

Section: Derepression Of Arx In Pdx1mentioning

confidence: 99%

The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine-cell specification and postnatal β-cell maturation

et al. 2016

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The transcription factor Pdx1 is required for multiple aspects of pancreatic organogenesis. It remains unclear to what extent Pdx1 expression and function depend upon trans-activation through 5′ conserved cis-regulatory regions and, in particular, whether the mammal-specific Area II (−2139 to −1958 bp) affects minor or major aspects of organogenesis. We show that Area II is a primary effector of endocrine-selective transcription in epithelial multipotent cells, nascent endocrine progenitors, and differentiating and mature β cells in vivo. Pdx1ΔAREAII/− mice exhibit a massive reduction in endocrine progenitor cells and progeny hormone-producing cells, indicating that Area II activity is fundamental to mounting an effective endocrine lineage-specification program within the multipotent cell population. Creating an Area II-deleted state within already specified Neurog3-expressing endocrine progenitor cells increased the proportion of glucagon + α relative to insulin + β cells, associated with the transcriptional and epigenetic derepression of the α-celldetermining Arx gene in endocrine progenitors. There were also glucagon and insulin co-expressing cells, and β cells that were incapable of maturation. Creating the Pdx1 ΔAREAII state after cells entered an insulin-expressing stage led to immature and dysfunctional islet β cells carrying abnormal chromatin marking in vital β-cell-associated genes. Therefore, trans-regulatory integration through Area II mediates a surprisingly extensive range of progenitor and β-cell-specific Pdx1 functions.

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Section: Derepression Of Arx In Pdx1mentioning

confidence: 99%

The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine-cell specification and postnatal β-cell maturation

et al. 2016

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“…We speculated that architectural molecules such as E-cad might represent potential direct targets of Pdx1. Analysis of published ChIP-on-chip and ChIP-Seq data obtained by other groups revealed that E-cad and β-cat promoters are bound by Pdx1 in isolated adult β-cells (Khoo et al, 2012;Teo et al, 2015), making these promising candidates. Our data provides further evidence that E-cad is a direct target of Pdx1.…”

Section: Discussionmentioning

confidence: 99%

Pdx1 regulates pancreas tubulogenesis and E-cadherin expression

Marty-Santos

Cleaver

2015

Development

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Current efforts in developing treatments for diabetes focus on in vitro generation of functional β-cells for cell replacement therapies; however, these attempts have only been partly successful because factors involved in islet formation remain incompletely understood. The embryonic pancreas, which gives rise to β-cells, undergoes early epithelial rearrangements, including transient stratification of an initially monolayered epithelium, followed by microlumen formation and later resolution into branches. Within the epithelium, a multipotent progenitor cell (MPC) population is specified, giving rise to three important lineages: acinar, ductal and endocrine. Pdx1 is a transcription factor required for pancreas development and lineage specification; however, few Pdx1 targets that regulate pancreatogenesis have been identified. We find that pancreatic defects in Pdx1 −/− embryos initiate at the time when the progenitor pool is specified and the epithelium should resolve into branches. Pdx1 −/− microlumen diameters expand aberrantly, resulting in failure of epithelial tubulogenesis and ductal plexus formation. Pdx1 −/− epithelial cell proliferation is decreased and the MPC pool is rapidly lost. We identify two conserved Pdx1 binding sites in the epithelial cadherin (E-cad, Cdh1) promoter, and show that Pdx1 directly binds and activates E-cad transcription. In addition, Pdx1 is required in vivo for maintenance of E-cad expression, actomyosin complex activity and cell shape. These findings demonstrate a novel link between regulators of epithelial architecture, specification of pancreatic cell fate and organogenesis.

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“…Ngn3 is a marker of endocrine progenitors [32, 33] and neogenesis [34, 35] in the adult pancreas. Additionally, Pdx1-expressing cells were confirmed in newly formed PIDs because Pdx1 is a critical transcription factor in the embryologic development [36, 37] and regeneration of the pancreas [38]. However, Pdx1 was not detected in PIDs derived from SSEA-4 + cells or CA19-9 + cells or in adult pancreatic ducts.…”

Section: Discussionmentioning

confidence: 99%

Adult human pancreas-derived cells expressing stage-specific embryonic antigen 4 differentiate into Sox9-expressing and Ngn3-expressing pancreatic ducts in vivo

Lee

Kim

2016

Stem Cell Res Ther

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BackgroundTissue-specific stem/progenitor cells are found in various adult tissues and may have the capacity for lineage-specific differentiation, facilitating applications in autologous transplantation. Stage-specific embryonic antigen 4 (SSEA-4), an early embryonic glycolipid antigen, is expressed in cells derived from adult human pancreas exocrine tissue. Here, we examined the characteristics and lineage-specific differentiation capacity of SSEA-4+ cells.MethodsHuman adult partial pancreas tissues were obtained from different donors and cultured in vitro. SSEA-4+ and CA19-9+ cells were isolated from adult human pancreas exocrine cells using magnetic-activated cell sorting, and gene expression was validated by quantitative polymerase chain reaction. To confirm in-vivo differentiation, SSEA-4+ and CA19-9+ cells were transplanted into the dorsal subcutaneous region of mice. Finally, morphological features of differentiated areas were confirmed by immunostaining and morphometric analysis.ResultsSSEA-4-expressing cells were detected in isolated pancreas exocrine cells from adult humans. These SSEA-4+ cells exhibited coexpression of CA19-9, a marker of pancreatic duct cells, but not amylase expression, as shown by immunostaining and flow cytometry. SSEA-4+ cells exhibited higher relative expression of Oct4, Nanog, Klf4, Sox2, and c-Myc mRNAs than CA19-9+ cells. Pancreatic intralobular ducts (PIDs) were generated from SSEA-4+ or CA19-9+ cells in vivo at 5 weeks after transplantation. However, newly formed PIDs from CA19-9+ cells were less abundant and showed an incomplete PID morphology. In contrast, newly formed PIDs from SSEA-4+ cells were abundant in the transplanted area and showed a crowded morphology, typical of PIDs. Sox9 and Ngn3, key transcription factors associated with pancreatic development and regeneration, were expressed in PIDs from SSEA-4+ cells.ConclusionsSSEA-4-expressing cells in the adult human pancreas may have the potential for regeneration of the pancreas and may be used as a source of stem/progenitor cells for pancreatic cell lineage-specific differentiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0422-0) contains supplementary material, which is available to authorized users.

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PDX1 Binds and Represses Hepatic Genes to Ensure Robust Pancreatic Commitment in Differentiating Human Embryonic Stem Cells

Cited by 48 publications

References 65 publications

The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine-cell specification and postnatal β-cell maturation

The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine-cell specification and postnatal β-cell maturation

Pdx1 regulates pancreas tubulogenesis and E-cadherin expression

Adult human pancreas-derived cells expressing stage-specific embryonic antigen 4 differentiate into Sox9-expressing and Ngn3-expressing pancreatic ducts in vivo

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