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.

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 (EfnB1OB-/-), 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 EfnB1OB-/- 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