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Intercellular Interactions of an Adipogenic CXCL12-Expressing Stromal Cell Subset in Murine Bone Marrow
Authors:Yuki Matsushita  Angel Ka Yan Chu  Wanida Ono  Joshua D Welch  Noriaki Ono
Affiliation:1. University of Michigan School of Dentistry, Ann Arbor, MI, USA

Contribution: Conceptualization, Data curation, Formal analysis, ​Investigation, Methodology, Resources, Validation, Visualization, Writing - original draft;2. Department of Computational Medicine and Bioinformatics, Department of Computer Science and Engineering, University of Michigan, Ann Arbor, MI, USA

Contribution: Formal analysis, Visualization, Writing - review & editing;3. University of Michigan School of Dentistry, Ann Arbor, MI, USA

Contribution: Funding acquisition, Resources, Writing - review & editing;4. Department of Computational Medicine and Bioinformatics, Department of Computer Science and Engineering, University of Michigan, Ann Arbor, MI, USA

Contribution: Formal analysis, ​Investigation, Methodology, Supervision, Visualization, Writing - review & editing;5. University of Michigan School of Dentistry, Ann Arbor, MI, USA

Abstract:
Bone marrow houses a multifunctional stromal cell population expressing C-X-C motif chemokine ligand 12 (CXCL12), termed CXCL12-abundant reticular (CAR) cells, that regulates osteogenesis and adipogenesis. The quiescent pre-adipocyte-like subset of CXCL12+ stromal cells (“Adipo-CAR” cells) is localized to sinusoidal surfaces and particularly enriched for hematopoiesis-supporting cytokines. However, detailed characteristics of these CXCL12+ pre-adipocyte-like stromal cells and how they contribute to marrow adipogenesis remain largely unknown. Here we highlight CXCL12-dependent physical coupling with hematopoietic cells as a potential mechanism regulating the adipogenic potential of CXCL12+ stromal cells. Single-cell computational analyses of RNA velocity and cell signaling reveal that Adipo-CAR cells exuberantly communicate with hematopoietic cells through CXCL12-CXCR4 ligand-receptor interactions but do not interconvert with Osteo-CAR cells. Consistent with this computational prediction, a substantial fraction of Cxcl12-creER+ pre-adipocyte-like cells intertwines with hematopoietic cells in vivo and in single-cell preparation in a protease-sensitive manner. Deletion of CXCL12 in these cells using Col2a1-cre leads to a reduction of stromal-hematopoietic coupling and extensive marrow adipogenesis in adult bone marrow, which appears to involve direct conversion of CXCL12+ cells to lipid-laden marrow adipocytes without altering mesenchymal progenitor cell fates. Therefore, these findings suggest that CXCL12+ pre-adipocyte-like marrow stromal cells prevent their premature differentiation by maintaining physical coupling with hematopoietic cells in a CXCL12-dependent manner, highlighting a possible cell-non-autonomous mechanism that regulates marrow adipogenesis. © 2021 American Society for Bone and Mineral Research (ASBMR).
Keywords:BONE–FAT INTERACTIONS  GENETIC ANIMAL MODELS  PRECLINICAL STUDIES  STROMAL/STEM CELLS
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