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PDX1+ cell budding morphogenesis in a stem cell-derived islet spheroid system

Author

Listed:
  • Jia Zhao

    (University of British Columbia)

  • Shenghui Liang

    (University of British Columbia)

  • Haoning Howard Cen

    (University of British Columbia)

  • Yanjun Li

    (Peking University)

  • Robert K. Baker

    (University of British Columbia)

  • Balwinder Ruprai

    (University of British Columbia)

  • Guang Gao

    (University of British Columbia)

  • Chloe Zhang

    (University of British Columbia)

  • Huixia Ren

    (Peking University
    Peking University)

  • Chao Tang

    (Peking University)

  • Liangyi Chen

    (Peking University
    Peking University)

  • Yanmei Liu

    (South China Normal University
    South China Normal University)

  • Francis C. Lynn

    (University of British Columbia)

  • James D. Johnson

    (University of British Columbia)

  • Timothy J. Kieffer

    (University of British Columbia
    University of British Columbia)

Abstract

Remarkable advances in protocol development have been achieved to manufacture insulin-secreting islets from human pluripotent stem cells (hPSCs). Distinct from current approaches, we devised a tunable strategy to generate islet spheroids enriched for major islet cell types by incorporating PDX1+ cell budding morphogenesis into staged differentiation. In this process that appears to mimic normal islet morphogenesis, the differentiating islet spheroids organize with endocrine cells that are intermingled or arranged in a core-mantle architecture, accompanied with functional heterogeneity. Through in vitro modelling of human pancreas development, we illustrate the importance of PDX1 and the requirement for EphB3/4 signaling in eliciting cell budding morphogenesis. Using this new approach, we model Mitchell-Riley syndrome with RFX6 knockout hPSCs illustrating unexpected morphogenesis defects in the differentiation towards islet cells. The tunable differentiation system and stem cell-derived islet models described in this work may facilitate addressing fundamental questions in islet biology and probing human pancreas diseases.

Suggested Citation

  • Jia Zhao & Shenghui Liang & Haoning Howard Cen & Yanjun Li & Robert K. Baker & Balwinder Ruprai & Guang Gao & Chloe Zhang & Huixia Ren & Chao Tang & Liangyi Chen & Yanmei Liu & Francis C. Lynn & James, 2024. "PDX1+ cell budding morphogenesis in a stem cell-derived islet spheroid system," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50109-2
    DOI: 10.1038/s41467-024-50109-2
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    References listed on IDEAS

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