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Mechanosignalling via integrins directs fate decisions of pancreatic progenitors

Author

Listed:
  • Anant Mamidi

    (University of Copenhagen)

  • Christy Prawiro

    (University of Copenhagen)

  • Philip A. Seymour

    (University of Copenhagen)

  • Kristian Honnens Lichtenberg

    (University of Copenhagen)

  • Abigail Jackson

    (University of Copenhagen)

  • Palle Serup

    (University of Copenhagen)

  • Henrik Semb

    (University of Copenhagen
    Helmholtz Zentrum München)

Abstract

The pancreas originates from two epithelial evaginations of the foregut, which consist of multipotent epithelial progenitors that organize into a complex tubular epithelial network. The trunk domain of each epithelial branch consists of bipotent pancreatic progenitors (bi-PPs) that give rise to both duct and endocrine lineages, whereas the tips give rise to acinar cells1. Here we identify the extrinsic and intrinsic signalling mechanisms that coordinate the fate-determining transcriptional events underlying these lineage decisions1,2. Single-cell analysis of pancreatic bipotent pancreatic progenitors derived from human embryonic stem cells reveal that cell confinement is a prerequisite for endocrine specification, whereas spreading drives the progenitors towards a ductal fate. Mechanistic studies identify the interaction of extracellular matrix (ECM) with integrin α5 as the extracellular cue that cell-autonomously, via the F-actin–YAP1–Notch mechanosignalling axis, controls the fate of bipotent pancreatic progenitors. Whereas ECM–integrin α5 signalling promotes differentiation towards the duct lineage, endocrinogenesis is stimulated when this signalling cascade is disrupted. This cascade can be disrupted pharmacologically or genetically to convert bipotent pancreatic progenitors derived from human embryonic stem cells to hormone-producing islet cells. Our findings identify the cell-extrinsic and intrinsic mechanotransduction pathway that acts as gatekeeper in the fate decisions of bipotent pancreatic progenitors in the developing pancreas.

Suggested Citation

  • Anant Mamidi & Christy Prawiro & Philip A. Seymour & Kristian Honnens Lichtenberg & Abigail Jackson & Palle Serup & Henrik Semb, 2018. "Mechanosignalling via integrins directs fate decisions of pancreatic progenitors," Nature, Nature, vol. 564(7734), pages 114-118, December.
    • Handle: RePEc:nat:nature:v:564:y:2018:i:7734:d:10.1038_s41586-018-0762-2
    DOI: 10.1038/s41586-018-0762-2
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    Cited by:

    1. Shakti Dahiya & Mohamed Saleh & Uylissa A. Rodriguez & Dhivyaa Rajasundaram & Jorge R. Arbujas & Arian Hajihassani & Kaiyuan Yang & Anuradha Sehrawat & Ranjeet Kalsi & Shiho Yoshida & Krishna Prasadan, 2024. "Acinar to β-like cell conversion through inhibition of focal adhesion kinase," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Mostafa Bakhti & Aimée Bastidas-Ponce & Sophie Tritschler & Oliver Czarnecki & Marta Tarquis-Medina & Eva Nedvedova & Jessica Jaki & Stefanie J. Willmann & Katharina Scheibner & Perla Cota & Ciro Sali, 2022. "Synaptotagmin-13 orchestrates pancreatic endocrine cell egression and islet morphogenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Ryan J. Geusz & Allen Wang & Dieter K. Lam & Nicholas K. Vinckier & Konstantinos-Dionysios Alysandratos & David A. Roberts & Jinzhao Wang & Samy Kefalopoulou & Araceli Ramirez & Yunjiang Qiu & Joshua , 2021. "Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    4. Feng Lin & Xia Li & Shiyu Sun & Zhongyi Li & Chenglin Lv & Jianbo Bai & Lin Song & Yizhao Han & Bo Li & Jianping Fu & Yue Shao, 2023. "Mechanically enhanced biogenesis of gut spheroids with instability-driven morphomechanics," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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