| Autor: |
KRISHNAMURTHY, MANSA, BRODA, TAYLOR R., ZHANG, XINGHAO, PALERMO, JOSEPH J., THOMAS, INAS H., HEIDER, AMER, STEIEN, DANA B., DAUBER, ANDREW, WELLS, JAMES |
| Zdroj: |
Diabetes; 2019 Supplement, Vol. 68, pN.PAG-N.PAG, 1p |
| Abstrakt: |
Pancreas and gastrointestinal (GI) tract development is guided by several transcription factors, including Pancreatic and duodenal homeobox gene-1 (PDX1). While it is well known that PDX1 is essential for pancreas development, its role in GI development and function in humans has not been investigated. We have identified two patients with a homozygous point mutation in PDX1 (c.188delC(p.P63fs)), causing total loss of protein function. These patients have additional GI complications however endoscopy and histological analysis of gastric and ?intestinal biopsies did not? reveal any pathologies. We used patient derived GI organoids from induced pluripotent stem cells (iPSCs) as a novel diagnostic approach and identified a myriad of undiagnosed GI pathologies. Analyses of human antral gastric organoids (HAGO) using immunofluorescence staining demonstrated a loss of gastric marker? claudin18 (CLDN18) and increased intestinal villin expression in PDX1-null? organoids, signifying that regions of the antrum are converting to an intestinal?phenotype. Similarly, human intestinal organoids (HIO) demonstrated a loss of intestinal marker ?Cadherin17 and an increase in gastric marker? CLDN18, indicating that regions of the intestine are undergoing gastric metaplasia. We also observed an increase in parietal cells in HAGOs, a lack of gastrin hormone in HAGO, and an increase in mucin production in HIOs. Based on this data we re-analyzed antral and duodenal biopsies of both patients and confirmed gastric and intestinal metaplasia increased parietal cells, decreased gastrin and increased mucin production. Because of our findings, these patients will have additional screening to monitor for development of gastric and intestinal cancer. This clearly demonstrates the utility of organoids in improving patient diagnoses and developing new clinical treatment plans. Disclosure: M. Krishnamurthy: None. T.R. Broda: None. X. Zhang: None. J.J. Palermo: None. I.H. Thomas: None. A. Heider: None. D.B. Steien: None. A. Dauber: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Novo Nordisk Inc. J. Wells: None. Funding: American Diabetes Association (1-19-PDF-036 to M.K.) [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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