title: Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation.
abstract: Large bone defects naturally regenerate via a highly vascularized tissue which progressively remodels into cartilage and bone. Current approaches in bone tissue engineering are restricted by delayed vascularization and fail to recapitulate this stepwise differentiation toward bone tissue. Here, we use the morphogen Sonic Hedgehog (Shh) to induce the in vitro organization of an endothelial capillary network in an artificial tissue. We show that endogenous Hedgehog activity regulates angiogenic genes and the formation of vascular lumens. Exogenous Shh further induces the in vitro development of the vasculature (vascular lumen formation, size, distribution). Upon implantation, the in vitro development of the vasculature improves the in vivo perfusion of the artificial tissue and is necessary to contribute to, and enhance, the formation of de novo mature bone tissue. Similar to the regenerating callus, the artificial tissue undergoes intramembranous and endochondral ossification and forms a trabecular-like bone organ including bone-marrow-like cavities. These findings open the door for new strategies to treat large bone defects by closely mimicking natural endochondral bone repair.
authors.affiliation: Department of Tissue Regeneration, MIRA Institute for Biomedical Technology and Technical Medicine, 7500AE, University of Twente, Enschede, The Netherlands. nicolasrivron@gmail.com
authors.forename: Nicolas C
authors.initials: NC
authors.lastname: Rivron
authors.forename: Christian C
authors.initials: CC
authors.lastname: Raiss
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Anandkumar
authors.initials: A
authors.lastname: Nandakumar
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Roman
authors.initials: R
authors.lastname: Truckenmüller
authors.forename: Jeroen
authors.initials: J
authors.lastname: Rouwkema
authors.forename: Clemens A
authors.initials: CA
authors.lastname: van Blitterswijk
mesh_terms: D000818:Animals; D001807:Blood Vessel Prosthesis; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation; D005109:Extracellular Matrix / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic; D010012:Osteogenesis; D044968:Regenerative Medicine / Q000379:methods; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*
chemical_list: D053823:Hedgehog Proteins