Intercellular Interactions of an Adipogenic CXCL12-Expressing Stromal Cell Subset in Murine Bone Marrow.
Intercellular Interactions of an Adipogenic CXCL12-Expressing Stromal Cell Subset in Murine Bone Marrow.
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DOI：
10.1002/jbmr.4282
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Ono N
中科院分区：
文献类型：
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作者：
Matsushita Y;Chu AKY;Ono W;Welch JD;Ono N
骨髓中有一个多功能的基质细胞群，表达C-X-C基序趋化因子配体12(CXCL12)，称为CXCL12丰富网状细胞(CAR)，调节成骨和脂肪生成。静止的CXCL12+基质细胞前脂肪细胞亚群(“Adipo-CAR”细胞)定位于正弦波表面，尤其富含支持造血的细胞因子。然而，这些CXCL12+前脂肪细胞样基质细胞的详细特征以及它们如何促进骨髓脂肪生成在很大程度上仍不清楚。在这里，我们强调CXCL12依赖的与造血细胞的物理偶联是调节CXCL12+基质细胞成脂潜力的潜在机制。RNA速度和细胞信号的单细胞计算分析表明，ADIPO-CAR细胞通过CXCL12-CXCR4配体-受体相互作用与造血细胞进行活跃的通讯，但不与Osteo-CAR细胞相互转换。与这一计算预测一致，相当一部分CXCL12-Creer+前脂肪细胞样细胞在体内和单细胞制剂中以蛋白酶敏感的方式与造血细胞交织在一起。使用Col2a1-cre缺失这些细胞中的CXCL12会导致基质-造血偶联减少，并导致成人骨髓广泛的脂肪生成，这似乎涉及CXCL12+细胞直接转化为富含脂肪的骨髓脂肪细胞，而不改变间充质祖细胞的命运。因此，这些发现表明，CXCL12+前脂肪细胞样骨髓基质细胞通过以CXCL12依赖的方式维持与造血细胞的物理偶联来防止其过早分化，突显了调节骨髓脂肪生成的可能的细胞非自主机制。
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.
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