Loss of EfnB1 in the osteogenic lineage compromises their capacity to support hematopoietic stem/progenitor cell maintenance

Agnieszka Arthur; Thao M Nguyen; Sharon Paton; Andrew C W Zannettino; Stan Gronthos

doi:10.1016/j.exphem.2018.10.004

Loss of EfnB1 in the osteogenic lineage compromises their capacity to support hematopoietic stem/progenitor cell maintenance

Exp Hematol. 2019 Jan:69:43-53. doi: 10.1016/j.exphem.2018.10.004. Epub 2018 Oct 13.

Authors

Agnieszka Arthur¹, Thao M Nguyen¹, Sharon Paton¹, Andrew C W Zannettino², Stan Gronthos³

Affiliations

¹ Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
² Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
³ Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia. Electronic address: [email protected].

PMID: 30326247
DOI: 10.1016/j.exphem.2018.10.004

Abstract

The bone marrow stromal microenvironment contributes to the maintenance and function of hematopoietic stem/progenitor cells (HSPCs). The Eph receptor tyrosine kinase family members have been implicated in bone homeostasis and stromal support of HSPCs. The present study examined the influence of EfnB1-expressing osteogenic lineage on HSPC function. Mice with conditional deletion of EfnB1 in the osteogenic lineage (EfnB1_OB^-/-), driven by the Osterix promoter, exhibited a reduced prevalence of osteogenic progenitors and osteoblasts, correlating to lower numbers of HSPCs compared with Osx:Cre mice. Long-term culture-initiating cell (LTC-IC) assays confirmed that the loss of EfnB1 within bone cells hindered HSPC function, with a significant reduction in colony formation in EfnB1_OB^-/- mice compared with Osx:Cre mice. Human studies confirmed that activation of EPHB2 on CD34⁺ HSPCs via EFNB1-Fc stimulation enhanced myeloid/erythroid colony formation, whereas functional blocking of either EPHB1 or EPHB2 inhibited the maintenance of LTC-ICs. Moreover, EFNB1 reverse signaling in human and mouse stromal cells was found to be required for the activation of the HSPC-promoting factor CXCL12. Collectively, the results of this study confirm that EfnB1 contributes to the stromal support of HSPC function and maintenance and may be an important factor in regulating the HSPC niche.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chemokine CXCL2 / genetics
Chemokine CXCL2 / metabolism
Ephrin-B1 / genetics
Ephrin-B1 / metabolism*
Gene Deletion
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / metabolism*
Humans
Mice
Mice, Knockout
Osteoblasts / cytology
Osteoblasts / metabolism*
Osteogenesis*
Signal Transduction*
Stem Cell Niche*
Stromal Cells / cytology
Stromal Cells / metabolism

Substances

CXCL2 protein, human
Chemokine CXCL2
Cxcl2 protein, mouse
EFNB1 protein, human
Efnb1 protein, mouse
Ephrin-B1