CXCL12-abundant reticular cell lineage is the key source of endosteal osteoblasts and adipocytes in adult bone marrow.

INTRODUCTION

CXCL12-abundant reticular (CAR) cells, characterized by high expression of CXCL12, are perisinusoidal bone marrow stromal cells that establish the hematopoietic stem cell niche. Although CAR cells are postulated to become precursor cells of both osteoblasts and adipocytes, the spatiotemporal dynamics of CAR cells-particularly their contribution to osteoblasts-remain poorly understood. Here, we defined the contribution of the endogenous Cxcl12-expressing (Cxcl12+) lineage to the skeleton from development to adulthood.

METHODS

A novel Cxcl12-Cre knock-in mouse model was generated that allows permanent lineage tracing of CAR cells and their progeny.

RESULTS

Lineage tracing revealed that the Cxcl12+ lineage arose perinatally and was initially localized around sinusoids in the bone marrow. During aging, these cells expanded and progressively populated non-sinusoidal regions distal to the sinusoids. While the contribution of the lineage to osteogenesis was negligible during postnatal growth, the lineage accounted for over 60% of endosteal osteoblasts in both cortical and trabecular bones in skeletally mature adult mice. Additionally, the lineage gave rise to the majority of bone marrow adipocytes. This lineage did not contribute to periosteal osteoblasts or extra-bone adipocytes. Furthermore, intermittent administration of the anabolic agent parathyroid hormone significantly promoted osteoblast differentiation from this lineage. Single-cell RNA sequencing confirmed the presence of both osteogenic and adipogenic precursors within the traced population.

CONCLUSIONS

The Cxcl12-expression-based lineage tracing approach revealed the CAR cell lineage as the key source of endosteal osteoblasts and adipocytes in adult bone marrow, suggesting their important role in skeletal homeostasis. This lineage may represent a promising therapeutic target for age-related bone diseases.