Circulating cells with osteogenic potential are physiologically mobilized into the fracture healing site in the parabiotic mice model

Abstract

Based on the accumulating evidence of osteogenic cells present in the systemic circulation, we hypothesized that circulating osteogenic connective tissue progenitors (CTPs) home to fracture site and contribute to skeletal repair. Parabiotic animals were formed by surgically conjoining transgenic mice constitutively expressing green fluorescent protein (GFP) in no erythroid tissue and syngeneic wild-type mice. After 3 weeks parabionts, equilibrium in blood chimerism between partners was established. A transverse fibular fracture was made in the contralateral hind limb of the conjoined wild-type partner. The contribution of circulating cells to the fracture callus was assessed based on analysis of GFPþ cells and co-localization of alkaline phosphatase (AP) staining nonfracture and at 1, 2, 3, and 4 weeks after fracture. Histomorphometric analysis at the fracture site showed significant increase of GFPþ cells after 2 (5.4%) and 3 (5.6%) weeks compared to nonfractured controls (1.7%). Of the GFPþ cells, percentage of the cells expressing AP activity at 1 (37.4%) and 2 (85.3%) weeks postfracture time was statistically higher than that in nonfractured controls (10.8%). The rate of mobilization of circulating osteogenic CTPs to fracture callus was also examined using 1 week parabionts at week 0-1 and week 1-2 postfracture. There was significant increase of GFPþ/APþ cells from week 0-1 (0.1%) and week 1-2 (1.8%). These data indicate that circulating osteogenic CTPs are mobilized to fracture site and contribute to osteogenesis in the early stage of fracture healing. ß

Stromal cell–derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model

“…Although the role of circulating MSCs in bone healing remains controversial, a recent study formally demonstrated the participation of circulating osteogenic connective tissue progenitor cells in a parabiotic mouse model of fracture healing (34). Moreover, another interesting study demonstrated that circulating bone Figure 5.…”

Circulating plastic adherent mesenchymal stem cells in aged hip fracture patients

“…[2][3][4][5][6][7]15 However, the significance and functional role of systemically recruited MSCs in fracture healing remain unknown.…”

“…Several experimental studies have suggested that circulating osteogenic cells may home in to sites of fracture repair. [4][5][6][7] Since the original description by Friedenstein and coworkers isolation of MSCs based on plastic adherence has become a standard. 8,9 MSCs can be isolated from many tissues, but their frequency in peripheral circulation seems extremely rare in human under normal conditions, on the order of 1 in 10 8 peripheral blood (PB) mononuclear cells (MNCs).…”

Adult Stem Cell Mobilization Enhances Intramembranous Bone Regeneration: A Pilot Study

“…These endogenous progenitor cells can be mobilized to the PB [1,11,12,15,17,22,36,48,52]. Circulating MSCs, and perhaps other adult stem cells, home to sites of skeletal injury [14,23,29,35,45,54], and increasing the number of adult stem cells at sites of injury aids tissue regeneration [4,8,16,40,43,56] either directly or through trophic effects [5,8,17,53].…”