EBF1-mutant bone marrow stroma confers long-term changes in hematopoietic stem cell potential [HSC]

Crosstalk between mesenchymal stromal cells (MSCs) and hematopoietic stem and cells (HSCs) is essential for hematopoietic homeostasis and lineage output. Here, we investigate the role of Early B-cell factor 1 (EBF1) in MSCs to support hematopoiesis. Ebf1-/- MSCs have reduced mesenchymal lineage potential. Ebf1 deletion in Cxcl12-abundant reticular (CAR) cells and PDGFRα+Sca1+CD45-CD31-Lin- (PαS) cells in the bone marrow decreases the numbers of HSPCs and myeloid cells. Single cell and bulk transcriptome analysis, combined with analysis of chromatin accessibility in EBF1-deficient MSCs revealed an altered niche composition and MSCs identity. In HSCs that were exposed to the EBF1-deficient niche, we detected an altered chromatin accessibility and impaired occupancy by AP-1, ETS and IRF proteins. Notably, the effects of the EBF1-deficient niche on HSPCs are retained after transfer to a wild-type niche. Thus, genetic alterations in the bone marrow niche can result in long-term changes of the chromatin landscape in HSCs.