1. Developmental Biology
  2. Stem Cells and Regenerative Medicine
Download icon

In Vivo imaging of β-cell function reveals glucose-mediated heterogeneity of β-cell functional development

Research Article
  • Cited 7
  • Views 3,692
  • Annotations
Cite this article as: eLife 2019;8:e41540 doi: 10.7554/eLife.41540

Abstract

How pancreatic β-cells acquire function in vivo is a long-standing mystery due to the lack of technology to visualize β-cell function in living animals. Here, we applied a high-resolution two-photon light-sheet microscope for the first in vivo imaging of Ca2+ activity of every β-cell in Tg (ins:Rcamp1.07) zebrafish. We reveal that the heterogeneity of β-cell functional development in vivo occurred as two waves propagating from the islet mantle to the core, coordinated by islet vascularization. Increasing amounts of glucose induced functional acquisition and enhancement of β-cells via activating calcineurin/nuclear factor of activated T-cells (NFAT) signalling. Conserved in mammalians, calcineurin/NFAT prompted high-glucose-stimulated insulin secretion of neonatal mouse islets cultured in vitro. However, the reduction in low-glucose-stimulated insulin secretion was dependent on optimal glucose but independent of calcineurin/NFAT. Thus, combination of optimal glucose and calcineurin activation represents a previously unexplored strategy for promoting functional maturation of stem cell-derived β-like cells in vitro.

Article and author information

Author details

  1. Jia Zhao

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1669-6992
  2. Weijian Zong

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yiwen Zhao

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Dongzhou Gou

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Shenghui Liang

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Jiayu Shen

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yi Wu

    School of Software and Microelectronics, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Xuan Zheng

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Runlong Wu

    School of Electronics Engineering and Computer Science, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Xu Wang

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Fuzeng Niu

    School of Electronics Engineering and Computer Science, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Aimin Wang

    School of Electronics Engineering and Computer Science, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Yunfeng Zhang

    School of Electronics Engineering and Computer Science, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Jing-Wei Xiong

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Liangyi Chen

    Institute of Molecular Medicine, Peking University, Beijing, China
    For correspondence
    lychen@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1270-7321
  16. Yanmei Liu

    Institute of Molecular Medicine, Peking University, Beijing, China
    For correspondence
    yanmeiliu@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9380-2560

Funding

National Science and Technology Major Project Program (2016YFA0500400)

  • Liangyi Chen

National Natural Science Foundation of China (91854112)

  • Yanmei Liu

National Natural Science Foundation of China (91750203)

  • Yanmei Liu

National Natural Science Foundation of China (31327901)

  • Liangyi Chen

National Natural Science Foundation of China (31521062)

  • Liangyi Chen

National Natural Science Foundation of China (31570839)

  • Liangyi Chen

National Natural Science Foundation of China (31301186)

  • Yanmei Liu

Beijing Natural Science Foundation (L172003)

  • Liangyi Chen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal care, generation of transgenic zebrafish lines, in vivo imaging of the live zebrafish embryos and all other experiments involving zebrafish and mouse islets were approved by the IACUC of Peking University in China (reference no. IMM-ChenLY-2).

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Publication history

  1. Received: August 29, 2018
  2. Accepted: January 29, 2019
  3. Accepted Manuscript published: January 29, 2019 (version 1)
  4. Version of Record published: February 28, 2019 (version 2)

Copyright

© 2019, Zhao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,692
    Page views
  • 556
    Downloads
  • 7
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Developmental Biology
    Xia Han et al.
    Research Article

    Cranial neural crest (CNC) cells give rise to bone, cartilage, tendons, and ligaments of the vertebrate craniofacial musculoskeletal complex, as well as regulate mesoderm-derived craniofacial muscle development through cell-cell interactions. Using the mouse soft palate as a model, we performed an unbiased single-cell RNA-seq analysis to investigate the heterogeneity and lineage commitment of CNC derivatives during craniofacial muscle development. We show that Runx2, a known osteogenic regulator, is expressed in the CNC-derived perimysial and progenitor populations. Loss of Runx2 in CNC-derivatives results in reduced expression of perimysial markers (Aldh1a2 and Hic1) as well as soft palate muscle defects in Osr2-Cre;Runx2fl/fl mice. We further reveal that Runx2 maintains perimysial marker expression through suppressing Twist1, and that myogenesis is restored in Osr2-Cre;Runx2fl/fl;Twist1fl/+ mice. Collectively, our findings highlight the roles of Runx2, Twist1, and their interaction in regulating the fate of CNC-derived cells as they guide craniofacial muscle development through cell-cell interactions.

    1. Developmental Biology
    Junjun Jing et al.
    Research Article

    Interaction between adult stem cells and their progeny is critical for tissue homeostasis and regeneration. In multiple organs, mesenchymal stem cells (MSCs) give rise to transit amplifying cells (TACs), which then differentiate into different cell types. However, whether and how MSCs interact with TACs remains unknown. Using the adult mouse incisor as a model, we present in vivo evidence that TACs and MSCs have distinct genetic programs and engage in reciprocal signaling cross talk to maintain tissue homeostasis. Specifically, an IGF-WNT signaling cascade is involved in the feedforward from MSCs to TACs. TACs are regulated by tissue-autonomous canonical WNT signaling and can feedback to MSCs and regulate MSC maintenance via Wnt5a/Ror2-mediated non-canonical WNT signaling. Collectively, these findings highlight the importance of coordinated bidirectional signaling interaction between MSCs and TACs in instructing mesenchymal tissue homeostasis, and the mechanisms identified here have important implications for MSC–TAC interaction in other organs.