Generation of human iPSC-derived beta cells to study the pathogenesis of type 1 diabetes and screen drugs in vitro

Scope of the method

The Method relates to
  • Human health
The Method is situated in
  • Basic Research
  • Translational - Applied Research
Type of method
  • In vitro - Ex vivo
This method makes use of
  • Human derived cells / tissues / organs
Specify the type of cells/tissues/organs
Fibroblasts and PBMCs

Description

Method keywords
  • Pancreatic beta cells
  • Type 1 diabetes
  • Monogenic forms of diabetes
  • Type 2 diabetes
  • iPSC-derived islet cells
  • Cytokines
  • apoptosis
  • Endoplasmic reticulum stress
Scientific area keywords
  • Induced pluripotent stem cells
  • Disease modelling
  • Diabetes research
  • Pathogenesis
  • Diabetes
  • Pancreatic beta cells
Method description

We used a 7-stage protocol to generate beta cells from human Induced Pluripotent Stem Cells (iPSC) and evaluated whether these cells are responsive to the pro-inflammatory cytokines (IFNγ, IL-1β, or IFNα) that play a role in type 1 diabetes (T1D). Our data show that human iPSC-derived beta cells respond to pro-inflammatory cytokines IL-1β + IFNγ and IFNα, by activating the same pathogenic processes as adult human primary beta cells. These cells thus provide a useful model to better understand the pathogenesis of T1D and screen for new drugs aiming to protect beta cells in early disease.

Lab equipment
  • - Incubator;
  • - Fluorescence microscope;
  • - Confocal microscope;
  • - Flow cytometer.
Method status
  • Published in peer reviewed journal

Pros, cons & Future potential

Advantages

These cells present some advantages over primary or clonal human beta cells:

  • -They can be generated on-demand from iPSCs, contrary to primary human islets that are much less readily available and are often isolated from older donors;
  • -It is possible to generate iPSC from somatic cells obtained from T1D patients, which will allow the study of molecular mechanisms underlying diabetes-associated SNPs (single nucleotide polymorphisms);
  • -They represent a valuable tool for the screening for new drugs that may protect beta cells against cytokine-induced cell death in early T1D;
  • -They express receptors for the pro-inflammatory cytokines IL-1β, IFNγ, and IFNα and respond to these cytokines—particularly to IFNγ + IL-1β - similarly to adult human islets, the “golden standard” in the field.
Challenges

At the end of the differentiation process, the beta cells are not yet fully mature, and secrete less insulin than adult beta cells.

Modifications

There are major efforts by different groups to improve the differentiation process, and it is highly probable that in the near future it will be possible to achieve iPSC-derived beta cells with a function that is closely similar to adult beta cells.

Future & Other applications

iPSC-derived islet cells may become also a valuable tool for the screening of new drugs to protect beta cells against cytokine-induced cell death in early T1D.

References, associated documents and other information

References

Demine, S., Schiavo, A.A., Marín-Cañas, S. et al. Pro-inflammatory cytokines induce cell death, inflammatory responses, and endoplasmic reticulum stress in human iPSC-derived beta cells. Stem Cell Res Ther 11, 7 (2020). https://doi.org/10.1186/s13287-019-1523-3

Igoillo-Esteve M, Oliveira AF, Cosentino C, Fantuzzi F, Demarez C, Toivoinen S, Hu A, Chintawar S, Lopes M, Pachera N, Cai Y, Abdulkarim B, Ray M, Marselli L, Marchetti P, Tariq M, Jonas J-C, Boscolo M, Pandolfo M, Eizirik DL, Cnop M Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia. J Clin Invest Insight, 5:e134221-40, 2020

De Franco E, Lytrivi M, Ibrahim H, Montaser H, Wakeling M, Fantuzzi F, Patel K, Demarez C, Cai Y, Igoillo-Esteve M, Cosentino C, Lithovius V, Vihinen H, Jokitalo E, Laver TH, Johnson MB, Sawatani T, Shakeri H, Pachera N, Halioglu B, Ozbek MN, Unal E, Yildirim R, Godbole T, Yildiz M, Aydin B, Bilheu A, Suzuki I, Flanagan SE, Vanderhaeghen P, Senee V, Julier C, Marchetti P, Eizirik DL, Ellard S, Saarimaki-Vire J, Otonkoski T, Cnop M, Hattersley AT YIPF5 mutations cause diabetes and microcephaly through disrupted ER-to-Golgi trafficking. J Clin Invest, 130:6338-6353, 2020

Associated documents
Links
ULB Center for Diabetes Research
Indiana Biosciences Research Institute

Contact person

Decio L. Eizirik

Organisations

Université libre de Bruxelles
Center for Diabetes Research
Belgium
Brussels Region

Indiana Biosciences Research Institute
Diabetes Center
United States