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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, Iannis Aifantis
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.