The bone marrow microenvironment at single-cell resolution

• Published in: Nature (London) Vol. 569; no. 7755; pp. 222 - 228
• Main Authors: Tikhonova, Anastasia N., Dolgalev, Igor, Hu, Hai, Sivaraj, Kishor K., Hoxha, Edlira, Cuesta-Domínguez, Álvaro, Pinho, Sandra, Akhmetzyanova, Ilseyar, Gao, Jie, Witkowski, Matthew, Guillamot, Maria, Gutkin, Michael C., Zhang, Yutong, Marier, Christian, Diefenbach, Catherine, Kousteni, Stavroula, Heguy, Adriana, Zhong, Hua, Fooksman, David R., Butler, Jason M., Economides, Aris, Frenette, Paul S., Adams, Ralf H., Satija, Rahul, Tsirigos, Aristotelis, Aifantis, Iannis
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-05-2019; Nature Publishing Group
• Subjects: 14/63; 14/69; 38/39; 38/91; 45/91; 631/136/142; 631/136/232; 631/532/1542; 64/110; 64/60; Adaptor Proteins, Signal Transducing - metabolism; Adipocytes - cytology; Adipocytes - metabolism; Analysis; Animals; Biocompatibility; Bioinformatics; Biomedical materials; Bone marrow; Bone Marrow - blood supply; Calcium-Binding Proteins - metabolism; Cell Differentiation; Cell Lineage; Cellular Microenvironment; Chemokines; Coding; Endothelium, Vascular - cytology; Female; Gene Expression Regulation; Genes; Genomes; Genomics; Growth factors; Health aspects; Hematopoiesis - genetics; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Heterogeneity; Homeostasis; Humanities and Social Sciences; Ligands; Male; Medical schools; Mice; multidisciplinary; Myeloid Cells - cytology; Myeloid Cells - metabolism; Osteoblasts - cytology; Osteoblasts - metabolism; Populations; Receptors, Notch - metabolism; RNA-Seq; Science; Science (multidisciplinary); Single-Cell Analysis; Stem Cell Niche - genetics; Stem cell research; Stem cell transplantation; Stem cells; Stress, Physiological - genetics; T cell receptors; Transcription; Transcriptome - genetics; Transgenic animals; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1104-8

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.
The transcriptional landscape of cell populations of the mouse bone marrow microenvironment, mapped at single-cell resolution, reveals cellular heterogeneity in this niche as well as substantial transcriptional remodelling under stress conditions.