4.8 Article

Single-cell transcriptomics of LepR-positive skeletal cells reveals heterogeneous stress-dependent stem and progenitor pools

Journal

EMBO JOURNAL
Volume 41, Issue 4, Pages -

Publisher

WILEY
DOI: 10.15252/embj.2021108415

Keywords

bone marrow stromal cells; LepR(+) cells; periosteum; single-cell RNA-seq; skeletal stem; progenitor cells

Funding

  1. National Key R&D Program on Stem Cell and Translational Research [2017YFA0106400, 2017YFC1001500, 2021YFA1100900]
  2. National Natural Science Foundation of China [91749124, 81772389, 82070108, 31871478, 32022023]
  3. Zhejiang Provincial Natural Science Foundation of China [LR18C060001]
  4. Fundamental Research Funds for the Central Universities [22120190149, 22120200411, kx0200020173386]
  5. Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai

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Leptin receptor (LepR)-positive cells in the bone marrow play a key role in maintaining homeostasis of the adult skeleton. Through genetic lineage tracing and single-cell RNA sequencing, researchers identified a Notch3(+) bone marrow sub-population associated with vasculatures. They also found dynamic changes in adipogenic, osteogenic, and periosteal lineages within this population under different conditions.
Leptin receptor (LepR)-positive cells are key components of the bone marrow hematopoietic microenvironment, and highly enrich skeletal stem and progenitor cells that maintain homeostasis of the adult skeleton. However, the heterogeneity and lineage hierarchy within this population has been elusive. Using genetic lineage tracing and single-cell RNA sequencing, we found that Lepr-Cre labels most bone marrow stromal cells and osteogenic lineage cells in adult long bones. Integrated analysis of Lepr-Cre-traced cells under homeostatic and stress conditions revealed dynamic changes of the adipogenic, osteogenic, and periosteal lineages. Importantly, we discovered a Notch3(+) bone marrow sub-population that is slow-cycling and closely associated with the vasculatures, as well as key transcriptional networks promoting osteo-chondrogenic differentiation. We also identified a Sca-1(+) periosteal sub-population with high clonogenic activity but limited osteo-chondrogenic potential. Together, we mapped the transcriptomic landscape of adult LepR(+) stem and progenitor cells and uncovered cellular and molecular mechanisms underlying their maintenance and lineage specification.

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