Perivascular osteoprogenitors are associated with transcortical channels of long bones

Abstract

Abstract Bone remodeling and regeneration are dependent on resident stem/progenitor cells with the ability to replenish mature osteoblasts and repair the skeleton. Using lineage tracing approaches, we identified a population of Dmp1+ cells that reside within cortical bone and are distinct from osteocytes. Our aims were to characterize this stromal population of transcortical perivascular cells (TPCs) in their resident niche and evaluate their osteogenic potential. To distinguish this population from osteoblasts/osteocytes, we crossed mice containing inducible DMP1CreERT2/Ai9 Tomato reporter (iDMP/T) with Col2.3GFP reporter (ColGFP), a marker of osteoblasts and osteocytes. We observed iDMP/T+;ColGFP− TPCs within cortical bone following tamoxifen injection. These cells were perivascular and located within transcortical channels. Ex vivo bone outgrowth cultures showed TPCs migrated out of the channels onto the plate and expressed stem cell markers such as Sca1, platelet derived growth factor receptor beta (PDGFRβ), and leptin receptor. In a cortical bone transplantation model, TPCs migrate from their vascular niche within cortical bone and contribute to new osteoblast formation and bone tube closure. Treatment with intermittent parathyroid hormone increased TPC number and differentiation. TPCs were unable to differentiate into adipocytes in the presence of rosiglitazone in vitro or in vivo. Altogether, we have identified and characterized a novel stromal lineage-restricted osteoprogenitor that is associated with transcortical vessels of long bones. Functionally, we have demonstrated that this population can migrate out of cortical bone channels, expand, and differentiate into osteoblasts, therefore serving as a source of progenitors contributing to new bone formation.