The bone marrow microenvironment at single-cell resolution

Anastasia N. Tikhonova (), Igor Dolgalev, Hai Hu, Kishor K. Sivaraj, Edlira Hoxha, Álvaro Cuesta-Domínguez, Sandra Pinho, Ilseyar Akhmetzyanova, Jie Gao, Matthew Witkowski, Maria Guillamot, Michael C. Gutkin, Yutong Zhang, Christian Marier, Catherine Diefenbach, Stavroula Kousteni, Adriana Heguy, Hua Zhong, David R. Fooksman, Jason M. Butler, Aris Economides, Paul S. Frenette, Ralf H. Adams, Rahul Satija, Aristotelis Tsirigos () and Iannis Aifantis ()
Additional contact information
Anastasia N. Tikhonova: NYU School of Medicine
Igor Dolgalev: NYU School of Medicine
Hai Hu: NYU School of Medicine
Kishor K. Sivaraj: Faculty of Medicine
Edlira Hoxha: NYU School of Medicine
Álvaro Cuesta-Domínguez: Columbia University
Sandra Pinho: Albert Einstein College of Medicine
Ilseyar Akhmetzyanova: Albert Einstein College of Medicine
Jie Gao: Regeneron Genetics Center
Matthew Witkowski: NYU School of Medicine
Maria Guillamot: NYU School of Medicine
Michael C. Gutkin: Hackensack University Medical Center
Yutong Zhang: Division of Advanced Research Technologies, NYU School of Medicine
Christian Marier: Division of Advanced Research Technologies, NYU School of Medicine
Catherine Diefenbach: NYU School of Medicine
Stavroula Kousteni: Columbia University
Adriana Heguy: NYU School of Medicine
Hua Zhong: NYU School of Medicine
David R. Fooksman: Albert Einstein College of Medicine
Jason M. Butler: Hackensack University Medical Center
Aris Economides: Regeneron Genetics Center
Paul S. Frenette: Albert Einstein College of Medicine
Ralf H. Adams: Faculty of Medicine
Rahul Satija: New York Genome Center
Aristotelis Tsirigos: NYU School of Medicine
Iannis Aifantis: NYU School of Medicine

Nature, 2019, vol. 569, issue 7755, 222-228

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1104-8

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