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Oncostatin M regulates hematopoietic stem cell (HSC) niches in the bone marrow to restrict HSC mobilization

Abstract

We show that pro-inflammatory oncostatin M (OSM) is an important regulator of hematopoietic stem cell (HSC) niches in the bone marrow (BM). Treatment of healthy humans and mice with granulocyte colony-stimulating factor (G-CSF) dramatically increases OSM release in blood and BM. Using mice null for the OSM receptor (OSMR) gene, we demonstrate that OSM provides a negative feed-back acting as a brake on HSPC mobilization in response to clinically relevant mobilizing molecules G-CSF and CXCR4 antagonist. Likewise, injection of a recombinant OSM molecular trap made of OSMR complex extracellular domains enhances HSC mobilization in poor mobilizing C57BL/6 and NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. Mechanistically, OSM attenuates HSC chemotactic response to CXCL12 and increases HSC homing to the BM signaling indirectly via BM endothelial and mesenchymal cells which are the only cells expressing OSMR in the BM. OSM up-regulates E-selectin expression on BM endothelial cells indirectly increasing HSC proliferation. RNA sequencing of HSCs from Osmr−/− and wild-type mice suggest that HSCs have altered cytoskeleton reorganization, energy usage and cycling in the absence of OSM signaling in niches. Therefore OSM is an important regulator of HSC niche function restraining HSC mobilization and anti-OSM therapy combined with current mobilizing regimens may improve HSPC mobilization for transplantation.

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Fig. 1: OSM protein is increased upon G-CSF induced HSPC mobilization in humans and mice.
Fig. 2: OSM is highly expressed by neutrophils in the mobilized BM.
Fig. 3: Enhanced HSPC mobilization in response to G-CSF in Osmr−/− mice.
Fig. 4: In vivo neutralization of OSM with OSM-trap enhances HSPC mobilization in response to G-CSF.
Fig. 5: Deletion of Osmr gene enhances HSPC mobilization in response to Plerixafor+G-CSF.
Fig. 6: OSMR is only expressed by stromal cells in the BM however HSPCs from Osmr−/− mice display increased chemotaxis in vitro and reduced BM homing in vivo.
Fig. 7: Differential expression of genes in sorted LKS + FLT3 CD48 HSCs from the BM of naïve WT and Osmr−/− mice.
Fig. 8: HSCs are more quiescent in Osmr−/− mice.

Data availability

The RNA sequencing datasets generated in this study are deposited to NCBI GEO database (GSE157579).

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Acknowledgements

This work was supported by project grant 1144062 from the National Health and Medical Research Council of Australia (NHMRC) (JPL, IGW) and by donations from the Mater Foundation. IGW and JPL are supported by Research Fellowships 1108352 and 1136130 respectively from the NHMRC. We thank Translational Research Institute flow cytometry core facility and biological resources facility for flow cytometry and animal experiments, the University of Queensland Protein Expression Facility for OSM-trap production, Angelika Christ from the University of Queensland Institute of Molecular Biosciences Sequencing Facility, Galaxy Australia for RNA sequencing, Adam Ewing for his advice in analyzing RNA sequencing data, and Igor Makunin from Queensland Facility for Advanced Bioinformatics-UQ for bioinformatics.

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KB coordinated the work, planned and performed the experiments, analyzed the data, interpreted results, wrote and edited the manuscript. CMG performed animal experiments, flow cytometry assays and analyzed data. SYL performed and analyzed human OSM ELISA experiments. HST analyzed RNA sequencing data. KAA assisted with IHC experiments. TM and WF and assisted with animal experiments, western blot and RT-qPCR assays. HB organized experiments on human samples and edited the manuscript. NAS, GMN, HB and IGW provided essential reagents and advice and edited the manuscript. JPL conceived the work, attracted competitive funding, helped with experimental design and analyses, interpreted the results, wrote and edited the manuscript.

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Correspondence to Jean-Pierre Lévesque.

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Bisht, K., McGirr, C., Lee, SY. et al. Oncostatin M regulates hematopoietic stem cell (HSC) niches in the bone marrow to restrict HSC mobilization. Leukemia (2021). https://doi.org/10.1038/s41375-021-01413-z

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