Aberrant proliferation and differentiation of glycogen storage disease type Ib mesenchymal stem cells

Glycogen storage disease type Ib (GSD‐Ib) is caused by mutations of the glucose‐6‐phosphate transporter (G6PT) and characterized by disrupted glucose homeostasis, neutropenia, and neutrophil dysfunction. To investigate the role of G6PT in human adipose‐derived mesenchymal stem cells (hMSCs), the G6P...

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Bibliographic Details
Published in:FEBS letters 2018-01, Vol.592 (2), p.162-171
Main Authors: Sim, Sang Wan, Park, Tae Sub, Kim, Sung‐Jo, Park, Byung‐Chul, Weinstein, David A., Lee, Young Mok, Jun, Hyun Sik
Format: Article
Language:English
Subjects:
Adipogenesis
Adipose Tissue - cytology
Adipose Tissue - metabolism
Antiporters - genetics
Cell Differentiation
Cell Proliferation
Cells, Cultured
CRISPR-Cas Systems
CRISPR‐Cas9
Cyclooxygenase 2 - metabolism
differentiation
Dinoprostone - metabolism
glucose‐6‐phophate transporter
Glycogen Storage Disease Type I - genetics
Glycolysis
human adipose‐derived mesenchymal stem cell
Humans
Mesenchymal Stem Cells - cytology
Mesenchymal Stem Cells - metabolism
Monosaccharide Transport Proteins - genetics
Osteogenesis
Phenotype
proliferation
Single-Cell Analysis
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Summary:Glycogen storage disease type Ib (GSD‐Ib) is caused by mutations of the glucose‐6‐phosphate transporter (G6PT) and characterized by disrupted glucose homeostasis, neutropenia, and neutrophil dysfunction. To investigate the role of G6PT in human adipose‐derived mesenchymal stem cells (hMSCs), the G6PT gene was mutated by CRISPR/Cas9 technology and single cell‐derived G6PT−/− hMSCs were established. G6PT−/− hMSCs have significantly increased cell proliferation but impaired adipogenesis and osteogenesis. These phenotypes are associated with two mechanisms: i) metabolic reprogramming in G6PT−/− hMSCs causing a metabolic shift toward glycolysis rather than oxidative phosphorylation and ii) increased cyclooxygenase‐2‐derived prostaglandin E2 secretion in G6PT−/− hMSCs. This study demonstrates that G6PT is essential for proliferation and differentiation of MSCs, providing important insights into the GSD‐Ib phenotypes.
ISSN:0014-5793
1873-3468
DOI:10.1002/1873-3468.12939