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.

间充质基质细胞 (MSCs) 和造血干细胞 (HSCs) 之间的串扰对于造血稳态和谱系输出至关重要。在这里，我们研究了骨髓 (BM) MSCs 的转录变化如何对 HSCs 产生持久影响。Cxcl12 丰富的网状 (CAR) 细胞和PDGFRα ^{+ Sca1 +} ( ^PαS ) 细胞的单细胞分析揭示了广泛的细胞异质性，但转录因子基因Ebf1的均匀表达。这些 MSC 中Ebf1的条件性缺失改变了它们的细胞组成、染色质结构和基因表达谱，包括粘附相关基因的表达降低。在功能上，基质特异性Ebf1失活导致 HSC 粘附受损，导致静止减少和骨髓输出减少。最值得注意的是，存在于Ebf1 缺陷生态位中的 HSC 在其细胞组成和染色质结构中发生了变化，这些变化在连续移植中持续存在。因此，BM 生态位中的遗传改变导致 HSC 的长期功能变化。