EBF1-deficient bone marrow stroma elicits persistent changes in HSC potential.
Marta DereckaJosip Stefan HermanPierre CauchySenthilkumar RamamoorthyEkaterina LuparDominic GrünRudolf GrosschedlPublished in: Nature immunology (2020)
Crosstalk between mesenchymal stromal cells (MSCs) and hematopoietic stem cells (HSCs) is essential for hematopoietic homeostasis and lineage output. Here, we investigate how transcriptional changes in bone marrow (BM) MSCs result in long-lasting effects on HSCs. Single-cell analysis of Cxcl12-abundant reticular (CAR) cells and PDGFRα+Sca1+ (PαS) cells revealed an extensive cellular heterogeneity but uniform expression of the transcription factor gene Ebf1. Conditional deletion of Ebf1 in these MSCs altered their cellular composition, chromatin structure and gene expression profiles, including the reduced expression of adhesion-related genes. Functionally, the stromal-specific Ebf1 inactivation results in impaired adhesion of HSCs, leading to reduced quiescence and diminished myeloid output. Most notably, HSCs residing in the Ebf1-deficient niche underwent changes in their cellular composition and chromatin structure that persist in serial transplantations. Thus, genetic alterations in the BM niche lead to long-term functional changes of HSCs.
Keyphrases
- bone marrow
- mesenchymal stem cells
- single cell
- transcription factor
- genome wide
- induced apoptosis
- stem cells
- umbilical cord
- poor prognosis
- gene expression
- rna seq
- cell cycle arrest
- copy number
- genome wide identification
- dna damage
- dna methylation
- endoplasmic reticulum stress
- cell therapy
- high throughput
- oxidative stress
- binding protein
- dendritic cells
- biofilm formation
- immune response
- wild type
- cell fate