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Live-animal imaging of native haematopoietic stem and progenitor cells

Author

Listed:
  • Constantina Christodoulou

    (Boston Children’s Hospital
    Harvard University
    Novartis Institutes for BioMedical Research)

  • Joel A. Spencer

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Massachusetts General Hospital
    University of California Merced)

  • Shu-Chi A. Yeh

    (Massachusetts General Hospital
    Massachusetts General Hospital)

  • Raphaël Turcotte

    (Massachusetts General Hospital
    Massachusetts General Hospital)

  • Konstantinos D. Kokkaliaris

    (ETH Zurich)

  • Riccardo Panero

    (University of Torino)

  • Azucena Ramos

    (Boston Children’s Hospital
    Harvard University)

  • Guoji Guo

    (Howard Hughes Medical Institute, Harvard Medical School)

  • Negar Seyedhassantehrani

    (University of California Merced)

  • Tatiana V. Esipova

    (University of Pennsylvania
    University of Pennsylvania)

  • Sergei A. Vinogradov

    (University of Pennsylvania
    University of Pennsylvania)

  • Sarah Rudzinskas

    (University of Rochester Medical Center)

  • Yi Zhang

    (University of Rochester Medical Center)

  • Archibald S. Perkins

    (University of Rochester Medical Center)

  • Stuart H. Orkin

    (Howard Hughes Medical Institute, Harvard Medical School)

  • Raffaele A. Calogero

    (University of Torino)

  • Timm Schroeder

    (ETH Zurich)

  • Charles P. Lin

    (Massachusetts General Hospital
    Massachusetts General Hospital)

  • Fernando D. Camargo

    (Boston Children’s Hospital
    Harvard University)

Abstract

The biology of haematopoietic stem cells (HSCs) has predominantly been studied under transplantation conditions1,2. It has been particularly challenging to study dynamic HSC behaviour, given that the visualization of HSCs in the native niche in live animals has not, to our knowledge, been achieved. Here we describe a dual genetic strategy in mice that restricts reporter labelling to a subset of the most quiescent long-term HSCs (LT-HSCs) and that is compatible with current intravital imaging approaches in the calvarial bone marrow3–5. We show that this subset of LT-HSCs resides close to both sinusoidal blood vessels and the endosteal surface. By contrast, multipotent progenitor cells (MPPs) show greater variation in distance from the endosteum and are more likely to be associated with transition zone vessels. LT-HSCs are not found in bone marrow niches with the deepest hypoxia and instead are found in hypoxic environments similar to those of MPPs. In vivo time-lapse imaging revealed that LT-HSCs at steady-state show limited motility. Activated LT-HSCs show heterogeneous responses, with some cells becoming highly motile and a fraction of HSCs expanding clonally within spatially restricted domains. These domains have defined characteristics, as HSC expansion is found almost exclusively in a subset of bone marrow cavities with bone-remodelling activity. By contrast, cavities with low bone-resorbing activity do not harbour expanding HSCs. These findings point to previously unknown heterogeneity within the bone marrow microenvironment, imposed by the stages of bone turnover. Our approach enables the direct visualization of HSC behaviours and dissection of heterogeneity in HSC niches.

Suggested Citation

  • Constantina Christodoulou & Joel A. Spencer & Shu-Chi A. Yeh & Raphaël Turcotte & Konstantinos D. Kokkaliaris & Riccardo Panero & Azucena Ramos & Guoji Guo & Negar Seyedhassantehrani & Tatiana V. Esip, 2020. "Live-animal imaging of native haematopoietic stem and progenitor cells," Nature, Nature, vol. 578(7794), pages 278-283, February.
  • Handle: RePEc:nat:nature:v:578:y:2020:i:7794:d:10.1038_s41586-020-1971-z
    DOI: 10.1038/s41586-020-1971-z
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    Citations

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    Cited by:

    1. Yinghui Li & Mei He & Wenshan Zhang & Wei Liu & Hui Xu & Ming Yang & Hexiao Zhang & Haiwei Liang & Wenjing Li & Zhaozhao Wu & Weichao Fu & Shiqi Xu & Xiaolei Liu & Sibin Fan & Liwei Zhou & Chaoqun Wan, 2023. "Expansion of human megakaryocyte-biased hematopoietic stem cells by biomimetic Microniche," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. S-C. A. Yeh & J. Hou & J. W. Wu & S. Yu & Y. Zhang & K. D. Belfield & F. D. Camargo & C. P. Lin, 2022. "Quantification of bone marrow interstitial pH and calcium concentration by intravital ratiometric imaging," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Yang Ping Kuo & César Nombela-Arrieta & Oana Carja, 2024. "A theory of evolutionary dynamics on any complex population structure reveals stem cell niche architecture as a spatial suppressor of selection," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Runfeng Miao & Harim Chun & Xing Feng & Ana Cordeiro Gomes & Jungmin Choi & João P. Pereira, 2022. "Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Yang Liu & Qi Chen & Hyun-Woo Jeong & Bong Ihn Koh & Emma C. Watson & Cong Xu & Martin Stehling & Bin Zhou & Ralf H. Adams, 2022. "A specialized bone marrow microenvironment for fetal haematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Raquel S. Pereira & Rahul Kumar & Alessia Cais & Lara Paulini & Alisa Kahler & Jimena Bravo & Valentina R. Minciacchi & Theresa Krack & Eric Kowarz & Costanza Zanetti & Parimala Sonika Godavarthy & Fa, 2023. "Distinct and targetable role of calcium-sensing receptor in leukaemia," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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