title: Osteoinductivity of engineered cartilaginous templates devitalized by inducible apoptosis.
abstract: The role of cell-free extracellular matrix (ECM) in triggering tissue and organ regeneration has gained increased recognition, yet current approaches are predominantly based on the use of ECM from fully developed native tissues at nonhomologous sites. We describe a strategy to generate customized ECM, designed to activate endogenous regenerative programs by recapitulating tissue-specific developmental processes. The paradigm was exemplified in the context of the skeletal system by testing the osteoinductive capacity of engineered and devitalized hypertrophic cartilage, which is the primordial template for the development of most bones. ECM was engineered by inducing chondrogenesis of human mesenchymal stromal cells and devitalized by the implementation of a death-inducible genetic device, leading to cell apoptosis on activation and matrix protein preservation. The resulting hypertrophic cartilage ECM, tested in a stringent ectopic implantation model, efficiently remodeled to form de novo bone tissue of host origin, including mature vasculature and a hematopoietic compartment. Importantly, cartilage ECM could not generate frank bone tissue if devitalized by standard "freeze & thaw" (F&T) cycles, associated with a significant loss of glycosaminoglycans, mineral content, and ECM-bound cytokines critically involved in inflammatory, vascularization, and remodeling processes. These results support the utility of engineered ECM-based devices as off-the-shelf regenerative niches capable of recruiting and instructing resident cells toward the formation of a specific tissue.
authors.affiliation: Department of Surgery and Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; and.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Bourgine
authors.affiliation: Department of Surgery and Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; and IRCCS Istituto Ortopedico Galeazzi, via R. Galeazzi 4, 20161 Milano, Italy.
authors.forename: Celeste
authors.initials: C
authors.lastname: Scotti
authors.affiliation: Department of Surgery and Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; and.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Pigeot
authors.affiliation: Department of Surgery and Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; and.
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Tchang
authors.affiliation: Department of Surgery and Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; and.
authors.forename: Atanas
authors.initials: A
authors.lastname: Todorov
authors.affiliation: Department of Surgery and Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; and ivan.martin@usb.ch.
authors.forename: Ivan
authors.initials: I
authors.lastname: Martin
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001861:Bone Regeneration; D002356:Cartilage / Q000502:physiology*; D002474:Cell-Free System; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D005615:Freezing; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010012:Osteogenesis; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D055114:X-Ray Microtomography; D055815:Young Adult
keywords: developmental engineering; endochondral; extracellular matrix; hematopoisesis; osteoinductive