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单细胞分辨率下的骨髓微环境。

The bone marrow microenvironment at single-cell resolution.

机构信息

Department of Pathology, NYU School of Medicine, New York, NY, USA.

Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA.

出版信息

Nature. 2019 May;569(7755):222-228. doi: 10.1038/s41586-019-1104-8. Epub 2019 Apr 10.

DOI:10.1038/s41586-019-1104-8
PMID:30971824
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6607432/
Abstract

The bone marrow microenvironment has a key role in regulating haematopoiesis, but its molecular complexity and response to stress are incompletely understood. Here we map the transcriptional landscape of mouse bone marrow vascular, perivascular and osteoblast cell populations at single-cell resolution, both at homeostasis and under conditions of stress-induced haematopoiesis. This analysis revealed previously unappreciated levels of cellular heterogeneity within the bone marrow niche and resolved cellular sources of pro-haematopoietic growth factors, chemokines and membrane-bound ligands. Our studies demonstrate a considerable transcriptional remodelling of niche elements under stress conditions, including an adipocytic skewing of perivascular cells. Among the stress-induced changes, we observed that vascular Notch delta-like ligands (encoded by Dll1 and Dll4) were downregulated. In the absence of vascular Dll4, haematopoietic stem cells prematurely induced a myeloid transcriptional program. These findings refine our understanding of the cellular architecture of the bone marrow niche, reveal a dynamic and heterogeneous molecular landscape that is highly sensitive to stress and illustrate the utility of single-cell transcriptomic data in evaluating the regulation of haematopoiesis by discrete niche populations.

摘要

骨髓微环境在调节造血过程中起着关键作用，但它的分子复杂性和对压力的反应仍不完全清楚。在这里，我们以单细胞分辨率绘制了小鼠骨髓血管、血管周和成骨细胞群体在稳态和应激诱导造血条件下的转录图谱。这项分析揭示了骨髓龛位内以前未被重视的细胞异质性水平，并确定了促造血生长因子、趋化因子和膜结合配体的细胞来源。我们的研究表明，龛位元素在应激条件下发生了相当大的转录重编程，包括血管周细胞的脂肪细胞偏向。在应激诱导的变化中，我们观察到血管 Notch delta 样配体（由 Dll1 和 Dll4 编码）下调。在没有血管 Dll4 的情况下，造血干细胞过早地诱导了一个髓系转录程序。这些发现完善了我们对骨髓龛位细胞结构的理解，揭示了一个动态且异质的分子景观，对压力高度敏感，并说明了单细胞转录组数据在评估离散龛位群体对造血的调节中的实用性。

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