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An In Ovo Model for Testing Insulin-mimetic Compounds
Published on: April 23, 2018
Development of novel cell lines of diabetic dysfunction model fit for cell-based screening tests of medicinal
Mikako Saito1, Aya Hayakawa, Nobuya Inagaki
1Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan, mikako@cc.tuat.ac.jp.
Abstract:
Pdx-1 and Irs-1, genes highly associated with diabetes onset, were knocked down in mouse embryonic stem (ES) cells in order to develop cell line models for diabetes. ES cells with different gene knockdown levels were induced to differentiate to the stage of insulin production. Among the cell lines that differentiated, we identified two in which the levels of expression of both genes were 20-40 % of that of control cells. These cell lines showed appreciable deficiencies in three characteristic malfunctions associated with diabetes, namely, insulin production, insulin reception signaling, and glucose-stimulated insulin secretion. These dysfunctions were consistent with results reported elsewhere from in vivo and in vitro studies. Both cell lines did not show any abnormal morphology such as size, shape, color, and surface roughness. No abnormal expression profiles for 17 genes relevant to diabetes were observed. Therefore, these cell lines fulfilled the criteria for a validated cell model for diabetes. The model cell lines developed here are promising biomaterials for cell-based screening tests of new medicines that may be effective in treating diabetes.
Insights
Researchers developed new diabetes cell models using mouse embryonic stem cells. These models mimic key diabetes malfunctions, offering a promising tool for drug screening and diabetes research.
Area of Science:
- Biotechnology
- Stem Cell Biology
- Diabetes Research
Background:
- Diabetes mellitus is a complex metabolic disorder.
- Key genes like Pdx-1 and Irs-1 are implicated in diabetes onset.
- Developing reliable cell models is crucial for studying diabetes pathogenesis.
Purpose of the Study:
- To create validated cell line models for diabetes research.
- To investigate the impact of Pdx-1 and Irs-1 gene knockdown on stem cell differentiation.
- To establish a platform for screening potential diabetes therapeutics.
Main Methods:
- Mouse embryonic stem (ES) cells were genetically modified to reduce Pdx-1 and Irs-1 gene expression.
- ES cells were induced to differentiate towards insulin-producing cells.
- Functional assays assessed insulin production, reception signaling, and glucose-stimulated insulin secretion.
Main Results:
- Two cell lines with 20-40% Pdx-1 and Irs-1 expression showed significant deficiencies in insulin production and secretion.
- These cell lines exhibited impaired insulin reception signaling, mirroring diabetes characteristics.
- No morphological abnormalities or aberrant expression of other diabetes-related genes were observed.
Conclusions:
- Validated cell line models for diabetes have been successfully developed.
- These models accurately replicate key diabetes-associated cellular dysfunctions.
- The developed cell lines serve as promising biomaterials for diabetes drug discovery and development.
