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

Current Diabetes Reports volume 17, Article number: 116 (2017) Cite this article

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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Affiliations

  1. Center for Endocrinology, Diabetes and Metabolism, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Katelyn Millette & Senta Georgia

  2. Departments of Pediatrics and Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Senta Georgia

  3. Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Senta Georgia

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  1. Katelyn Millette
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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