The bone marrow microenvironment at single-cell resolution

Nature. 2019 May;569(7755):222-228. doi: 10.1038/s41586-019-1104-8. Epub 2019 Apr 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adipocytes / cytology
  • Adipocytes / metabolism
  • Animals
  • Bone Marrow / blood supply*
  • Calcium-Binding Proteins / metabolism
  • Cell Differentiation
  • Cell Lineage
  • Cellular Microenvironment*
  • Endothelium, Vascular / cytology
  • Female
  • Gene Expression Regulation
  • Hematopoiesis* / genetics
  • Hematopoietic Stem Cells* / cytology
  • Hematopoietic Stem Cells* / metabolism
  • Male
  • Mice
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • RNA-Seq
  • Receptors, Notch / metabolism
  • Single-Cell Analysis*
  • Stem Cell Niche* / genetics
  • Stress, Physiological / genetics
  • Transcriptome / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • Dlk1 protein, mouse
  • Receptors, Notch