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Exploring the effect of epigenetic modifiers on developing insulin-secreting cells

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Abstract

Diabetes is a worldwide health problem with increasing incidence. The current management modalities did not succeed to decrease comorbidities. This study aimed at enhancing the regenerative solution for diabetes by improving the differentiation of mesenchymal stromal cells (MSC) into glucose-sensitive, insulin-secreting cells through an epigenetic modification approach. A 3-day treatment protocol with the epigenetic modifiers, either decitabine (5-aza-2′-deoxycytidine; Aza); a DNA methylation inhibitor or Vorinostat (suberoylanilide hydroxamic acid; SAHA); a histone deacetylase inhibitor was added to two different human stem cell lines. The cells followed a multi-step differentiation protocol that provided the critical triggers in a temporal approach. Aza-pretreated group showed higher intracellular expression of insulin and the transcription factor ‘PDX-1’. The cells responded to the high glucose challenge by secreting insulin in the media, as shown by ELISA. Gene expression showed induction of the genes for insulin, the glucose transporter 2, glucokinase, as well as the transcription factors MafA and NKX6.1. Although SAHA showed upregulation of insulin secretion, in comparison to control, the cells could not respond to the high glucose challenge. Interestingly, Aza-treated cells showed a significant decrease in the global DNA methylation level at the end of the culture. In conclusion, this additional step with Aza could enhance the response of MSC to the classical differentiation protocol for insulin-secreting cells and may help in establishing a regenerative solution for patients with diabetes.

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Acknowledgements

This study was funded by Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences (Grant no.: MRG-6112013-2014). The laboratory infrastructure and personnel were supported by the University of Sharjah, UAE.

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Author notes

  1. Ibrahim Elsharkawi and Divyasree Parambath contributed equally.

Authors and Affiliations

  1. College of Medicine, University of Sharjah, Sharjah, UAE

    Ibrahim Elsharkawi, Maha Saber-Ayad & Ahmed T. El-Serafi

  2. Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE

    Divyasree Parambath & Maha Saber-Ayad

  3. College of Medicine, Cairo University, Cairo, Egypt

    Maha Saber-Ayad

  4. Department of Applied Biology, College of Science, University of Sharjah, Sharjah, UAE

    Amir Ali Khan

  5. Faculty of Medicine, Suez Canal University, Ismailia, Egypt

    Ahmed T. El-Serafi

  6. Department of Hand Surgery and Plastic Surgery and Burns, 401A, Building 462, Floor 11, Linköping University Hospital, P. O. Box: 581 85, Linköping, Sweden

    Ahmed T. El-Serafi

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  1. Ibrahim Elsharkawi
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  2. Divyasree Parambath
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Correspondence to Ahmed T. El-Serafi.

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Elsharkawi, I., Parambath, D., Saber-Ayad, M. et al. Exploring the effect of epigenetic modifiers on developing insulin-secreting cells. Human Cell 33, 1–9 (2020). https://doi.org/10.1007/s13577-019-00292-y

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