Thrombopoietin from hepatocytes promotes hematopoietic stem cell regeneration after myeloablation

  1. Longfei Gao
  2. Matthew Decker
  3. Haidee Chen
  4. Lei Ding  Is a corresponding author
  1. Columbia University, United States

Abstract

The bone marrow niche plays a critical role in hematopoietic recovery and hematopoietic stem cell (HSC) regeneration after myeloablative stress. However, it is not clear whether systemic factors beyond the local niche are required for these essential processes in vivo. Thrombopoietin (THPO) is a critical cytokine promoting hematopoietic rebound after myeloablation and its transcripts are expressed by multiple cellular sources. The upregulation of bone marrow-derived THPO has been proposed to be crucial for hematopoietic recovery and HSC regeneration after stress. Nonetheless, the cellular source of THPO in myeloablative stress has never been investigated genetically. We assessed the functional sources of THPO following two common myeloablative perturbations: 5-fluorouracil (5-FU) administration and irradiation. Using a Thpo translational reporter, we found that the liver but not the bone marrow is the major source of THPO protein after myeloablation. Mice with conditional Thpo deletion from osteoblasts and/or bone marrow stromal cells showed normal recovery of HSCs and hematopoiesis after myeloablation. In contrast, mice with conditional Thpo deletion from hepatocytes showed significant defects in HSC regeneration and hematopoietic rebound after myeloablation. Thus, systemic THPO from the liver is necessary for HSC regeneration and hematopoietic recovery in myeloablative stress conditions.

Data availability

All data were presented with individual data points from each mouse. Source data files have been provided for Figure 1-4. No sequencing or diffraction data are generated.

Article and author information

Author details

  1. Longfei Gao

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Matthew Decker

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Haidee Chen

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Lei Ding

    Columbia University, New York, United States
    For correspondence
    ld2567@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4869-8877

Funding

National Heart, Lung, and Blood Institute (R01HL132074)

  • Lei Ding

National Heart, Lung, and Blood Institute (R01HL153487)

  • Lei Ding

National Heart, Lung, and Blood Institute (R01HL155868)

  • Lei Ding

New York State Stem Cell Science (Training grant)

  • Longfei Gao

National Heart, Lung, and Blood Institute (1F30HL137323)

  • Matthew Decker

Rita Allen Foundation (Scholar Award)

  • Lei Ding

Irma T. Hirschl Trust

  • Lei Ding

Leukemia and Lymphoma Society (Scholar Award)

  • Lei Ding

National Cancer Institute (P30CA013696)

  • Longfei Gao
  • Matthew Decker
  • Haidee Chen
  • Lei Ding

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

Ethics

Animal experimentation: All mice were housed in specific pathogen-free, Association for the Assessment andAccreditation of Laboratory Animal Care (AAALAC)- approved facilities at the ColumbiaUniversity Medical Center. All protocols were approved by the Institute Animal Care and UseCommittee of Columbia University under AC-AAAZ9451.

Copyright

© 2021, Gao 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.

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  1. Longfei Gao
  2. Matthew Decker
  3. Haidee Chen
  4. Lei Ding
(2021)
Thrombopoietin from hepatocytes promotes hematopoietic stem cell regeneration after myeloablation
eLife 10:e69894.
https://doi.org/10.7554/eLife.69894

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https://doi.org/10.7554/eLife.69894