Gene Editing and Human Pluripotent Stem Cells: Tools for Advancing Diabetes Disease Modeling and Beta-Cell Development

Abstract

Purpose of Review

This review will focus on the multiple approaches to gene editing and address the potential use of genetically modified human pluripotent stem cell-derived beta cells (SC-β) as a tool to study human beta-cell development and model their function in diabetes. We will explore how new variations of CRISPR/Cas9 gene editing may accelerate our understanding of beta-cell developmental biology, elucidate novel mechanisms that establish and regulate beta-cell function, and assist in pioneering new therapeutic modalities for treating diabetes.

Recent Findings

Improvements in CRISPR/Cas9 target specificity and homology-directed recombination continue to advance its use in engineering stem cells to model and potentially treat disease. We will review how CRISPR/Cas9 gene editing is informing our understanding of beta-cell development and expanding the therapeutic possibilities for treating diabetes and other diseases.

Summary

Here we focus on the emerging use of gene editing technology, specifically CRISPR/Cas9, as a means of manipulating human gene expression to gain novel insights into the roles of key factors in beta-cell development and function. Taken together, the combined use of SC-β cells and CRISPR/Cas9 gene editing will shed new light on human beta-cell development and function and accelerate our progress towards developing new therapies for patients with diabetes.

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Fig. 1

Abbreviations

iPSC:

Induced pluripotent stem cell

SC-β:

Human pluripotent stem cell-derived beta cells

hPSC:

Human pluripotent stem cell

ESC:

Embryonic stem cell

HR:

Homologous recombination

NHEJ:

Non-homologous end-joining

ZFN:

Zinc finger nucleases

TALEN:

Transcription activator-like effector nucleases

CRISPR:

Clustered regularly interspaced short palindromic repeats

sgRNA:

Single-guide RNA

DSB:

Double-strand break

GWAS:

Genome-wide association study

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Acknowledgements

We thank Cristy Lytal for her help in editing the manuscript. SG was supported by a Larry L. Hillblom Foundation grant (2015-D-006-SUP) and a California Institute for Regenerative Medicine Discovery grant (DISC1-088680).

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Katelyn Millette and Senta Georgia declare that they have no conflicts of interest.

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Millette, K., Georgia, S. Gene Editing and Human Pluripotent Stem Cells: Tools for Advancing Diabetes Disease Modeling and Beta-Cell Development. Curr Diab Rep 17, 116 (2017). https://doi.org/10.1007/s11892-017-0947-3

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Keywords

  • Diabetes
  • Gene editing
  • CRISPR/Cas9
  • Pluripotent stem cells
  • Cellular therapy
  • Disease modeling
  • Beta cells
  • Insulin