Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Nat Immunol. 2020 Mar;21(3):261-273. doi: 10.1038/s41590-020-0595-7. Epub 2020 Feb 17.
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 PDGFRαSca1 (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 中的转录变化如何导致对 HSCs 的持久影响。Cxcl12 丰富的网状（CAR）细胞和 PDGFRαSca1（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 的表达一致。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。功能上，基质特异性的 Ebf1 失活导致 HSCs 的粘附受损，导致静止减少和髓样输出减少。最值得注意的是，存在于 Ebf1 缺陷龛中的 HSCs经历了细胞组成和染色质结构的变化，这些变化在连续移植中持续存在。因此，BM 龛位中的遗传改变导致 HSCs 的长期功能变化。
