Perivascular osteoprogenitors are associated with transcortical channels of long bones

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. K E Y W O R D S cortical channel, dentin matrix protein-1 (DMP1), osteoprogenitor, transplantation

The diverse origin of bone-forming osteoblasts

“…Dmp1 + perivascular cells can migrate out of the transcortical channel and expand and differentiate into osteoblasts in bone organ cultures. ( 91 )…”

“…( 103,104 ) These observations were confirmed by a lineage‐tracing study using Dmp1‐creER , which can label the descendants of mature osteoblasts after a long chase, including bone‐lining cells and osteocytes. ( 105 ) Root et al ( 91 ) identified that Dmp1‐creER ‐labeled perivascular osteoprogenitors localized in the trans‐cortical channel are mobilized by PTH treatment and increase mature osteoblasts. These results indicate that the diverse origins of osteoblasts contribute to the PTH‐induced bone anabolic actions.…”

Acid Dentin Lysate Failed to Modulate Bone Formation in Rat Calvaria Defects

“…Initially, augmentation procedures often involved the use of autologous bone obtained from the same patient, either alone or combined with bone substitutes to subsequently allow the placement of dental implants [ 2 ]. Autologous bone is a favorable graft because of its osteoconductive properties [ 3 ], osteogenic activity [ 4 , 5 ], and source of growth factors stored in the matrix [ 6 ]. However, the limited amount of local autologous bone and the morbidity upon harvesting [ 7 ] has stimulated the search for alternative sources of these bone substitutes including allografts and xenografts.…”

Intermittent PTH Administration Increases Bone-Specific Blood Vessels and Surrounding Stromal Cells in Murine Long Bones

“…It is plausible, therefore, that vascular smooth muscle cells may still have some potential for trans-differentiation [16,18,20]. Bone arteries are in fact reportedly covered with SMA-positive cells that have the potential to differentiate into one of many mesenchymal lineages including osteoblasts [21][22][23][24].…”