Thrombopoietin from hepatocytes promotes hematopoietic stem cell regeneration after myeloablation
- 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
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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Thrombopoietin from hepatocytes promotes hematopoietic stem cell regeneration after myeloablation
eLife 10:e69894.
https://doi.org/10.7554/eLife.69894
