The bone marrow microenvironment at single-cell resolution
Open accessAbstract
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.
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Loss of the vascular-endothelial-expressed Notch ligand DLL4 skews HSPC differentiation toward myelopoiesis.
“They particularly showed that the loss of the vascular-endothelial-expressed Notch ligand DLL4 skews HSPC differentiation toward myelopoiesis.42”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [42]
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- Authors
- Tikhonova, A. N., Dolgalev, I., Hu, H., Sivaraj, K. K., Hoxha, E., Cuesta-Domínguez, Á., Pinho, S., Akhmetzyanova, I., Gao, J., Witkowski, M., Guillamot, M., Gutkin, M. C., Zhang, Y., Marier, C., Diefenbach, C., Kousteni, S., Heguy, A., Zhong, H., Fooksman, D. R., Butler, J. M., Economides, A., Frenette, P. S., Adams, R. H., Satija, R., Tsirigos, A., & Aifantis, I.
- Affiliations
- NYU Langone Health (US)
- University of Münster (DE)
- Albert Einstein College of Medicine (US)
- Regeneron (United States) (US)
- Hackensack University Medical Center (US)
- Columbia University (US)
- New York Genome Center (US)
- Corresponding author
- Tikhonova, Anastasia N.
- Tsirigos, Aristotelis
- Aifantis, Iannis
- ORCID
- Tikhonova, Anastasia N.
- Dolgalev, Igor
- Hu, Hai
- Sivaraj, Kishor K.
- Pinho, Sandra
- Akhmetzyanova, Ilseyar
- Gao, Jie
- Witkowski, Matthew
- Gutkin, Michael C.
- Zhang, Yutong
- Diefenbach, Catherine
- Kousteni, Stavroula
- Heguy, Adriana
- Fooksman, David R.
- Butler, Jason M.
- Economides, Aris
- Frenette, Paul S.
- Adams, Ralf H.
- Satija, Rahul
- Tsirigos, Aristotelis
- Aifantis, Iannis
- Venue
- Nature
- Published
- 2019-04-10
- Volume
- 569
- Issue
- 7755
- Pages
- 222-228
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6607432
- OpenAlex
- W2936664461
- Cited by
- 936
- References
- 73
- Citations by year
- 2026: 89 · 2025: 106 · 2024: 113 · 2023: 153 · 2022: 129 · 2021: 153 · 2020: 137 · 2019: 56
- FWCI
- 83.83
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-07-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- NYU Langone Medical Center
- Nature
- National Institutes of Health (1dp2hg009623-01)
- National Heart, Lung, and Blood Institute (R01HL130937, R01HL069438)
- National Human Genome Research Institute (DP2-HG-009623)
- National Cancer Institute (R01CA194923, R01CA202027, R01CA202025, R01CA169784, R01CA105129)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK112976, R01DK056638, U01DK116312)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- bone marrow microenvironment, hematopoiesis, hematopoietic stem cells, single-cell transcriptomics, perivascular cells, osteoblasts, vascular cells, DLL4, DLL1, Notch signaling, myeloid differentiation, chemokines, growth factors, cellular heterogeneity
- MeSH terms
- RNA-Seq, Animals, Bone Marrow, Calcium-Binding Proteins, Cell Differentiation, Endothelium, Vascular, Female, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Male, Osteoblasts, Stress, Physiological, Adipocytes, Cell Lineage, Myeloid Cells, Adaptor Proteins, Signal Transducing, Mice, Receptors, Notch, Stem Cell Niche, Single-Cell Analysis, Transcriptome, Cellular Microenvironment
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