title: Chondrogenic priming of human bone marrow stromal cells: a better route to bone repair?
abstract: The use of bioengineered cell constructs for the treatment of bone defects has received much attention of late. Often, bone marrow stromal cells (BMSCs) are used that are in vitro-stimulated toward the osteogenic lineage, aiming at intramembranous bone formation. The success of this approach has been disappointing. A major concern with these constructs is core degradation and necrosis caused by lack of vascularization. We hypothesized that stimulation of cells toward the endochondral ossification process would be more successful. In this study, we tested how in vitro priming of human BMSCs (hBMSCs) along osteogenic and chondrogenic lineages influences survival and osteogenesis in vivo. Scaffolds that were pre-cultured on chondrogenic culture medium showed collagen type II and collagen type X production. Moreover, vessel ingrowth was observed. Priming along the osteogenic lineage led to a mineralized matrix of poor quality, with few surviving cells and no vascularization. We further characterized this process in vitro using pellet cultures. In vitro, pellets cultured in chondrogenic medium showed progressive production of collagen type II and collagen type X. In the culture medium of these chondrogenic cultured pellets, vascular endothelial growth factor (VEGF) release was observed at days 14, 21, and 35. When pellets were switched to culture medium containing beta-glycerophosphate, independent of the presence or absence of transforming growth factor beta (TGF-beta), mineralization was observed with a concomitant reduction in VEGF and matrix metalloproteinase (MMP) release. By showing that VEGF and MMPs are produced in chondrogenically differentiated hBMSCs in vitro, we demonstrated that these cells produce factors that are known to be important for the induction of vascularization of the matrix. Inducing mineralization in this endochondral process does, however, severely diminish these capacities. Taken together, these data suggest that optimizing chondrogenic priming of hBMSCs may further improve vessel invasion in bioengineered constructs, thus leading to an alternative and superior approach to bone repair.
authors.affiliation: Erasmus MC, University Medical Centre Rotterdam , the Netherlands Department of Orthopaedics, Rotterdam, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Farrell
authors.forename: Olav P
authors.initials: OP
authors.lastname: van der Jagt
authors.forename: Wendy
authors.initials: W
authors.lastname: Koevoet
authors.forename: Nicole
authors.initials: N
authors.lastname: Kops
authors.forename: Christiaan J
authors.initials: CJ
authors.lastname: van Manen
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Hellingman
authors.forename: Holger
authors.initials: H
authors.lastname: Jahr
authors.forename: Fergal J
authors.initials: FJ
authors.lastname: O'Brien
authors.forename: Jan A N
authors.initials: JA
authors.lastname: Verhaar
authors.forename: Harrie
authors.initials: H
authors.lastname: Weinans
authors.forename: Gerjo J V M
authors.initials: GJ
authors.lastname: van Osch
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology* / Q000201:enzymology; D001842:Bone and Bones / Q000473:pathology*; D020219:Chondrogenesis; D024043:Collagen Type II / Q000378:metabolism; D024121:Collagen Type X / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010012:Osteogenesis; D019919:Prosthesis Implantation; D013194:Staining and Labeling; D017154:Stromal Cells / Q000166:cytology* / Q000201:enzymology; D054457:Tissue Scaffolds; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
chemical_list: D024043:Collagen Type II; D024121:Collagen Type X; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases