Document Type
Article
Publication Date
2-1-2024
Original Citation
Schwartz L,
Young K,
Stearns T,
Boyer N,
Mujica K,
Trowbridge JJ.
Transcriptional and functional consequences of Oncostatin M signaling on young Dnmt3a-mutant hematopoietic stem cells. Exp Hematol. 2024;130:104131.
Keywords
JMG, SS1, Animals, Mice, Anti-Inflammatory Agents, Bone Marrow, Hematopoiesis, Hematopoietic Stem Cells, Oncostatin M
JAX Source
Exp Hematol. 2024;130:104131.
ISSN
1873-2399
PMID
38000729
DOI
https://doi.org/10.1016/j.exphem.2023.11.005
Grant
This work was supported by National Institutes of Health (Bethesda, MD, USA) Grants R01DK118072, R01AG069010, and U01AG077925 and a grant from the Edward P. Evans Foundation (Andover, MA, USA) to J.J.T. This work was supported in part by the National Cancer Institute (Bethesda, MD, USA) Cancer Center Sup- port Grant P30CA034196. J.J.T. was supported by a Leukemia & Lymphoma Society (Rye Brook, NY, USA) Scholar Award and The Dattels Family Endowed Chair. L.S.S. was supported by National Institutes of Health (Bethesda, MD, USA) F31DK127573 and The Tufts University Scheer-Tomasso Fund philanthropic gift.
Abstract
Age-associated clonal hematopoiesis (CH) occurs due to somatic mutations accrued in hematopoietic stem cells (HSCs) that confer a selective growth advantage in the context of aging. The mechanisms by which CH-mutant HSCs gain this advantage with aging are not comprehensively understood. Using unbiased transcriptomic approaches, we identified Oncostatin M (OSM) signaling as a candidate contributor to age-related Dnmt3a-mutant CH. We found that Dnmt3a-mutant HSCs from young adult mice (3-6 months old) subjected to acute OSM stimulation do not demonstrate altered proliferation, apoptosis, hematopoietic engraftment, or myeloid differentiation. Dnmt3a-mutant HSCs from young mice do transcriptionally upregulate an inflammatory cytokine network in response to acute in vitro OSM stimulation as evidenced by significant upregulation of the genes encoding IL-6, IL-1β, and TNFα. OSM-stimulated Dnmt3a-mutant HSCs also demonstrate upregulation of the anti-inflammatory genes Socs3, Atf3, and Nr4a1. In the context of an aged bone marrow (BM) microenvironment, Dnmt3a-mutant HSCs upregulate proinflammatory genes but not the anti-inflammatory genes Socs3, Atf3, and Nr4a1. The results from our studies suggest that aging may exhaust the regulatory mechanisms that HSCs employ to resolve inflammatory states in response to factors such as OSM.
Comments
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)