title: Systemic mesenchymal stem cell administration enhances bone formation in fracture repair but not load-induced bone formation.
abstract: Mesenchymal stem cells (MSC) were shown to support bone regeneration, when they were locally transplanted into poorly healing fractures. The benefit of systemic MSC transplantation is currently less evident. There is consensus that systemically applied MSC are recruited to the site of injury, but it is debated whether they actually support bone formation. Furthermore, the question arises as to whether circulating MSC are recruited only in case of injury or whether they also participate in mechanically induced bone formation. To answer these questions we injected green fluorescent protein (GFP)-labelled MSC into C57BL/6J mice, which were subjected either to a femur osteotomy or to non-invasive mechanical ulna loading to induce bone formation. We detected GFP-labelled MSC in the early (day 10) and late fracture callus (day 21) by immunohistochemistry. Stromal cell-derived factor 1 (SDF-1 or CXCL-12), a key chemokine for stem cell attraction, was strongly expressed by virtually all cells near the osteotomy--indicating that SDF-1 may mediate cell migration to the site of injury. We found no differences in SDF-1 expression between the groups. Micro-computed tomography (µCT) revealed significantly more bone in the callus of the MSC treated mice compared to untreated controls. The bending stiffness of callus was not significantly altered after MSC-application. In contrast, we failed to detect GFP-labelled MSC in the ulna after non-invasive mechanical loading. Histomorphometry and µCT revealed a significant load-induced increase in bone formation; however, no further increase was found after MSC administration. Concluding, our results suggest that systemically administered MSC are recruited and support bone formation only in case of injury but not in mechanically induced bone formation.
authors.affiliation: Institute of Orthopaedic Research and Biomechanics, Helmholtzstr. 14, 89081 Ulm, Germany.anna.rapp@uni-ulm.de.
authors.forename: A E
authors.initials: AE
authors.lastname: Rapp
authors.forename: R
authors.initials: R
authors.lastname: Bindl
authors.forename: A
authors.initials: A
authors.lastname: Heilmann
authors.forename: A
authors.initials: A
authors.lastname: Erbacher
authors.forename: I
authors.initials: I
authors.lastname: Müller
authors.forename: R E
authors.initials: RE
authors.lastname: Brenner
authors.forename: A
authors.initials: A
authors.lastname: Ignatius
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D002146:Bony Callus / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D017102:Fracture Healing; D050723:Fractures, Bone / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010012:Osteogenesis; D013997:Time Factors; D055114:X-Ray Microtomography
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D049452:Green Fluorescent Proteins