Pericytes as a Source of Osteogenic Cells in Bone Fracture Healing

Abstract

Pericytes are mesenchymal cells that surround the endothelial cells of small vessels in various organs. These cells express several markers, such as NG2, CD146, and PDGFRβ, and play an important role in the stabilization and maturation of blood vessels. It was also recently revealed that like mesenchymal stem cells (MSCs), pericytes possess multilineage differentiation capacity, especially myogenic, adipogenic, and fibrogenic differentiation capacities. Although some previous studies have reported that pericytes also have osteogenic potential, the osteogenesis of pericytes can still be further elucidated. In the present study, we established novel methods for isolating and culturing primary murine pericytes. An immortalized pericyte line was also established. Multilineage induction of the pericyte line induced osteogenesis, adipogenesis, and chondrogenesis of the cells in vitro. In addition, pericytes that were injected into the fracture site of a bone fracture mouse model contributed to callus formation. Furthermore, in vivo pericyte-lineage-tracing studies demonstrated that endogenous pericytes also differentiate into osteoblasts and osteocytes and contribute to bone fracture healing as a cellular source of osteogenic cells. Pericytes can be a promising therapeutic candidate for treating bone fractures with a delayed union or nonunion as well as bone diseases causing bone defects.

Calcium-Sensing Receptors in Chondrocytes and Osteoblasts Are Required for Callus Maturation and Fracture Healing in Mice

“…There is, however, continuous, albeit delayed, progression of fracture repair in bony calluses of Tam-Cart CaSR Δflox/Δflox mice, which have drastically reduced numbers of chondrocyte-derived (ie, tdTomato(+)) OB (Fig. Indeed, osteoprogenitors derived from periosteum, (13) muscle, (13)(14)(15) pericyte, (16) and bone marrow stromal cells (17)(18)(19) have been shown to be critical in mediating the repair of both fixed and unfixed fractures in animal models. Indeed, osteoprogenitors derived from periosteum, (13) muscle, (13)(14)(15) pericyte, (16) and bone marrow stromal cells (17)(18)(19) have been shown to be critical in mediating the repair of both fixed and unfixed fractures in animal models.…”

“…4B), suggesting that the osteogenic activity through recruitment of other osteoprogenitors is also required for fracture repair. Indeed, osteoprogenitors derived from periosteum, (13) muscle, (13)(14)(15) pericyte, (16) and bone marrow stromal cells (17)(18)(19) have been shown to be critical in mediating the repair of both fixed and unfixed fractures in animal models. It is unclear whether the CaSR is involved in recruitment or commitment of mesenchymal cells to osteoprogenitors during fracture repair.…”

“…(7) Committed chondrocytes progress sequentially through stages of proliferation, maturation, hypertrophy, and terminal differentiation in columns of cells within the growth plate (GP) before the terminally differentiated chondrocytes transition into the osteoblastic lineage to form bone in spongiosa and other bone sites. In addition to endochondral bone formation, "membranous bone formation" also critically mediates bone repair, particularly in fixed fractures, through actions of osteoprogenitors/osteoblasts derived from periosteum, (13) muscle, (13)(14)(15) pericyte, (16) bone marrow (17)(18)(19) and commit to osteogenic lineage directly without transition through chondrogenic phase. At the later stages, osteogenic and osteoclastic activities take over to bridge and remodel the disrupted bony elements, returning them to the prior normal shape and strength.…”

“…However, cartilage within a callus has a transient existence (days to weeks), whereas GPs function for years until long bone growth ceases. In addition to endochondral bone formation, "membranous bone formation" also critically mediates bone repair, particularly in fixed fractures, through actions of osteoprogenitors/osteoblasts derived from periosteum, (13) muscle, (13)(14)(15) pericyte, (16) bone marrow (17)(18)(19) and commit to osteogenic lineage directly without transition through chondrogenic phase.…”

Identification of key microRNAs and target genes for the diagnosis of bone nonunion

“…Bone nonunion (Bn) is a frequent complication following bone fracture, occurring when fracture healing ceases without suitable bone union (1)(2)(3). While much research is required to fully elucidate the causes of Bn (4), the rate of Bn incidence continues to rise, with ≤10% of bone fracture patients estimated to have suffered from Bn (5).…”