Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
EMBO J. 2022 Feb 15;41(4):e108415. doi: 10.15252/embj.2021108415. Epub 2021 Dec 27.
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.
瘦素受体 (LepR)-阳性细胞是骨髓造血微环境的关键组成部分，高度富集维持成年骨骼内稳态的骨骼干细胞和祖细胞。然而，该群体内的异质性和谱系层次结构一直难以捉摸。使用遗传谱系追踪和单细胞 RNA 测序，我们发现 Lepr-Cre 标记成年长骨中大多数骨髓基质细胞和成骨谱系细胞。在稳态和应激条件下对 Lepr-Cre 追踪细胞的综合分析揭示了脂肪生成、成骨和骨膜谱系的动态变化。重要的是，我们发现了一个 Notch3 骨髓亚群，该亚群具有缓慢的细胞周期和与脉管系统的密切关联，以及促进成骨-软骨分化的关键转录网络。我们还鉴定了一个具有高克隆形成活性但成骨-软骨分化潜力有限的 Sca-1 骨膜亚群。总之，我们绘制了成年 LepR 干细胞和祖细胞的转录组图谱，并揭示了它们维持和谱系特化的细胞和分子机制。
