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EMBO J. 2015 Jul 2;34(13):1759-72. doi: 10.15252/embj.201591058. Epub 2015 Apr 23.

Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro.

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Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences and Department of Urology, University of California San Francisco, San Francisco, CA, USA.
Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Brehm Tower Ann Arbor, MI, USA.
Diabetes and Obesity Center of Excellence, Department of Medicine, Institute for Stem Cells and Regenerative Medicine, University of Washington, Seattle, WA, USA.
Diabetes Center, University of California San Francisco, San Francisco, CA, USA


Directed differentiation of human pluripotent stem cells into functional insulin-producing beta-like cells holds great promise for cell replacement therapy for patients suffering from diabetes. This approach also offers the unique opportunity to study otherwise inaccessible aspects of human beta cell development and function in vitro. Here, we show that current pancreatic progenitor differentiation protocols promote precocious endocrine commitment, ultimately resulting in the generation of non-functional polyhormonal cells. Omission of commonly used BMP inhibitors during pancreatic specification prevents precocious endocrine formation while treatment with retinoic acid followed by combined EGF/KGF efficiently generates both PDX1(+) and subsequent PDX1(+)/NKX6.1(+) pancreatic progenitor populations, respectively. Precise temporal activation of endocrine differentiation in PDX1(+)/NKX6.1(+) progenitors produces glucose-responsive beta-like cells in vitro that exhibit key features of bona fide human beta cells, remain functional after short-term transplantation, and reduce blood glucose levels in diabetic mice. Thus, our simplified and scalable system accurately recapitulates key steps of human pancreas development and provides a fast and reproducible supply of functional human beta-like cells.


beta‐like cells; diabetes; human embryonic stem cells; insulin‐producing cells, pancreas

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