1. The bone marrow microenvironment at single-cell resolution.
- Author
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Tikhonova AN, Dolgalev I, Hu H, Sivaraj KK, Hoxha E, Cuesta-Domínguez Á, Pinho S, Akhmetzyanova I, Gao J, Witkowski M, Guillamot M, Gutkin MC, Zhang Y, Marier C, Diefenbach C, Kousteni S, Heguy A, Zhong H, Fooksman DR, Butler JM, Economides A, Frenette PS, Adams RH, Satija R, Tsirigos A, and Aifantis I
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Adipocytes cytology, Adipocytes metabolism, Animals, Calcium-Binding Proteins metabolism, Cell Differentiation, Cell Lineage, Endothelium, Vascular cytology, Female, Gene Expression Regulation, Male, Mice, Myeloid Cells cytology, Myeloid Cells metabolism, Osteoblasts cytology, Osteoblasts metabolism, RNA-Seq, Receptors, Notch metabolism, Stress, Physiological genetics, Transcriptome genetics, Bone Marrow blood supply, Cellular Microenvironment, Hematopoiesis genetics, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Single-Cell Analysis, Stem Cell Niche genetics
- 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.
- Published
- 2019
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