CFCF Patient Education Michael Y. Choi, MD September 12, 2009 Using gastrin producing G-cell and its...
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Transcript of CFCF Patient Education Michael Y. Choi, MD September 12, 2009 Using gastrin producing G-cell and its...
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
Mucous Cell Parietal Cell
Gastroendocrine Cell Chief Cell
Gastric Lineages
Stomach Stem Cell
Nkx6.3 Expression
Decreased G-cell Number in the Nkx6.3-null Stomach
Abrogated Gastrin mRNA Expression in Nkx6.3 Stomach
Physiology Review of G- and D-cells
Co-localization of Nkx6.3 and Gastrin in the Stomach
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
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
Relative expression levels of Pdx1, Pax6, and Ngn3 mRNA are unchanged in adult Nkx6.3-null stomach
Nkx6.3 mRNA levels are unchanged in neonatal Ngn3-null antrum
Modified from Hochedlinger, K. et al. Development 2009
The developmental potential and epigenetic states of cells at different stages of development
PancreasStomach
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
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
Generating insulin secreting cells by direct reprogramming
• Expressed 3 genes Ngn3, Pdx1, Mafa to generate -cells from exocrine cells
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.?
Nkx6.3 upregulates Gastrin in 293 cells
Gastrinoma
Endoscopic view and a nest of tumor cells in lamina propria mucosae
Acknowledgement
• Ramesh Shivdasani• Maina Lepourcelet• Anthony Romer• Qiufu Ma• Paul Grey
• Melissa Wu• Andrew Leiter• Yang Wang• Susumu Ito• Byeong-Moo Kim• Daniel Podolsky