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A method for the generation of human stem cell-derived alpha cells

Author

Listed:
  • Quinn P. Peterson

    (Harvard University
    Mayo Clinic
    Mayo Clinic)

  • Adrian Veres

    (Harvard University)

  • Lihua Chen

    (AstraZeneca)

  • Michael Q. Slama

    (Mayo Clinic)

  • Jennifer H. R. Kenty

    (Harvard University)

  • Shaimaa Hassoun

    (Mayo Clinic)

  • Matthew R. Brown

    (Mayo Clinic)

  • Haiqiang Dou

    (University of Gothenburg)

  • Caden D. Duffy

    (Mayo Clinic)

  • Quan Zhou

    (Harvard University)

  • Aleksey V. Matveyenko

    (Mayo Clinic)

  • Björn Tyrberg

    (AstraZeneca
    University of Gothenburg
    Institut de Recherches Servier)

  • Maria Sörhede-Winzell

    (AstraZeneca)

  • Patrik Rorsman

    (University of Gothenburg
    University of Oxford)

  • Douglas A. Melton

    (Harvard University)

Abstract

The generation of pancreatic cell types from renewable cell sources holds promise for cell replacement therapies for diabetes. Although most effort has focused on generating pancreatic beta cells, considerable evidence indicates that glucagon secreting alpha cells are critically involved in disease progression and proper glucose control. Here we report on the generation of stem cell-derived human pancreatic alpha (SC-alpha) cells from pluripotent stem cells via a transient pre-alpha cell intermediate. These pre-alpha cells exhibit a transcriptional profile similar to mature alpha cells and although they produce proinsulin protein, they do not secrete significant amounts of processed insulin. Compound screening identified a protein kinase c activator that promotes maturation of pre-alpha cells into SC-alpha cells. The resulting SC-alpha cells do not express insulin, share an ultrastructure similar to cadaveric alpha cells, express and secrete glucagon in response to glucose and some glucagon secretagogues, and elevate blood glucose upon transplantation in mice.

Suggested Citation

  • Quinn P. Peterson & Adrian Veres & Lihua Chen & Michael Q. Slama & Jennifer H. R. Kenty & Shaimaa Hassoun & Matthew R. Brown & Haiqiang Dou & Caden D. Duffy & Quan Zhou & Aleksey V. Matveyenko & Björn, 2020. "A method for the generation of human stem cell-derived alpha cells," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16049-3
    DOI: 10.1038/s41467-020-16049-3
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    Cited by:

    1. Lihua Chen & Nannan Wang & Tongran Zhang & Feng Zhang & Wei Zhang & Hao Meng & Jingyi Chen & Zhiying Liao & Xiaopeng Xu & Zhuo Ma & Tao Xu & Huisheng Liu, 2024. "Directed differentiation of pancreatic δ cells from human pluripotent stem cells," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Jolanta Chmielowiec & Wojciech J. Szlachcic & Diane Yang & Marissa A. Scavuzzo & Katrina Wamble & Alejandro Sarrion-Perdigones & Omaima M. Sabek & Koen J. T. Venken & Malgorzata Borowiak, 2022. "Human pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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