Intercellular Interactions of an Adipogenic CXCL12 ‐Expressing Stromal Cell Subset in Murine Bone Marrow

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).