Format

Send to

Choose Destination
Nat Commun. 2018 Jul 11;9(1):2681. doi: 10.1038/s41467-018-04918-x.

Discovery of a drug candidate for GLIS3-associated diabetes.

Author information

1
Weill Graduate School of Medical Sciences of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
2
Department of Surgery, 1300 York Avenue, New York, NY, 10065, USA.
3
Division of Regenerative Medicine, Department of Medicine, Ansary Stem Cell Institute, 1300 York Avenue, New York, NY, 10065, USA.
4
Genomics Resources Core Facility, 1300 York Avenue, New York, NY, 10065, USA.
5
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
6
Developmental Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY, 10065, USA.
7
SKI Stem Cell Research Facility, Sloan Kettering Institute, New York, NY, 10065, USA.
8
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.
9
Developmental Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY, 10065, USA. huangfud@mskcc.org.
10
Weill Graduate School of Medical Sciences of Cornell University, 1300 York Avenue, New York, NY, 10065, USA. shc2034@med.cornell.edu.
11
Department of Surgery, 1300 York Avenue, New York, NY, 10065, USA. shc2034@med.cornell.edu.
12
Department of Biochemistry, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA. shc2034@med.cornell.edu.

Abstract

GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3-/- β-like cells have been unsuccessful. Here, we develop a "minimal component" protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3-/- hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.

PMID:
29992946
PMCID:
PMC6041295
DOI:
10.1038/s41467-018-04918-x
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center