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CFCF Patient Education
Michael Y. Choi, MD
September 12, 2009
Using gastrin producing G-cell and its essential gene Nkx6.3 as a model
to study gastrinoma
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Mucous Cell Parietal Cell
Gastroendocrine Cell Chief Cell
Gastric Lineages
Stomach Stem Cell
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Nkx6.3 Expression
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Decreased G-cell Number in the Nkx6.3-null Stomach
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Abrogated Gastrin mRNA Expression in Nkx6.3 Stomach
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Physiology Review of G- and D-cells
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Co-localization of Nkx6.3 and Gastrin in the Stomach
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Serum Gastrin Gastric pH
Wild type(N = 7)
Knockout(N = 7)
Wild type(N = 16)
Knockout(N = 7)
Mean 87.1 ng/L 37.7 ng/L 3.9 5.5
SEM 11.0 ng.L 10.8 ng/L 0.3 0.3
P-value 0.0075 0.0032
Circulating gastrin levels and stomach luminal pH in Nkx6.3-/- and control animals
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Mutant mice strains that have altered G-cell numbers
Gastric Endocrine Cell Type Number in KO Mutant
KO Strain Ref. Gastrin Somatostatin Serotonin Ghrelin
Pdx1 -/- Larsson et al. Down Unchanged Up
Pax6 -/- Larsson et al. Down Down Unchanged
Ngn3 -/- Jenny et al. Down Down Unchanged Unchanged
Lee et al. Down Down Down
CCK-B/Gastrin Receptor -/-
Langhans et al. Up Down
Gastrin -/- Zavros et al. Down Unchanged
Nkx6.3 -/- Down Up Unchanged Unchanged
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Relative expression levels of Pdx1, Pax6, and Ngn3 mRNA are unchanged in adult Nkx6.3-null stomach
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Nkx6.3 mRNA levels are unchanged in neonatal Ngn3-null antrum
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Modified from Hochedlinger, K. et al. Development 2009
The developmental potential and epigenetic states of cells at different stages of development
PancreasStomach
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Generating induced pluripotent stem cells by direct reprogramming
• Showed that iPS cells can be generated from mouse fibroblasts by retrovirus-mediated introduction of four transcription factors:
- Sox2, Oct4, Klf4, and c-Myc
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Yamanaka: Convert tail fibroblasts into pluripotent cells
resembling embryonic stem cells by expressing 4 genes:Oct4
Sox2Klf4cMyc
• “An Astonishing Experiment”
– Ian Wilmut,
Cloning and Stem Cells
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Generating insulin secreting cells by direct reprogramming
• Expressed 3 genes Ngn3, Pdx1, Mafa to generate -cells from exocrine cells
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Cell Reprogamming: what’s the limit?
-CellsExcocrine Cells Ngn3, Pdx1, Mafa
?Cancer Cells ?
Stem CellsFibroblastsSox2, Oct4, Klf4, Myc
G-Cells (or any cell type)Non G-Cells
Nkx6.3, Pdx1, Ngn3, Pax6, etc.?
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Nkx6.3 upregulates Gastrin in 293 cells
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Gastrinoma
Endoscopic view and a nest of tumor cells in lamina propria mucosae
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Acknowledgement
• Ramesh Shivdasani• Maina Lepourcelet• Anthony Romer• Qiufu Ma• Paul Grey
• Melissa Wu• Andrew Leiter• Yang Wang• Susumu Ito• Byeong-Moo Kim• Daniel Podolsky