title: Tissue engineered humanized bone supports human hematopoiesis in vivo.
abstract: Advances in tissue-engineering have resulted in a versatile tool-box to specifically design a tailored microenvironment for hematopoietic stem cells (HSCs) in order to study diseases that develop within this setting. However, most current in vivo models fail to recapitulate the biological processes seen in humans. Here we describe a highly reproducible method to engineer humanized bone constructs that are able to recapitulate the morphological features and biological functions of the HSC niches. Ectopic implantation of biodegradable composite scaffolds cultured for 4 weeks with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone organ including a large number of human mesenchymal cells which were shown to be metabolically active and capable of establishing a humanized microenvironment supportive of the homing and maintenance of human HSCs. A syngeneic mouse-to-mouse transplantation assay was used to prove the functionality of the tissue-engineered ossicles. We predict that the ability to tissue engineer a morphologically intact and functional large-volume bone organ with a humanized bone marrow compartment will help to further elucidate physiological or pathological interactions between human HSCs and their native niches.
authors.affiliation: Regenerative Medicine Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4049, Brisbane, Australia; Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97074 Wuerzburg, Germany.
authors.forename: Boris M
authors.initials: BM
authors.lastname: Holzapfel
authors.affiliation: Regenerative Medicine Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4049, Brisbane, Australia; George W Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive Northwest, Atlanta, GA 30332, USA; Institute for Advanced Study, Technical University Munich, Lichtenbergstraße 2a, 85748 Garching, Munich, Germany. Electronic address: dietmar.hutmacher@qut.edu.au.
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Hutmacher
authors.affiliation: Stem Cell Biology Group and Stem Cells and Cancer Group - Blood and Bone Diseases Program, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Brisbane, Australia.
authors.forename: Bianca
authors.initials: B
authors.lastname: Nowlan
authors.affiliation: Stem Cell Biology Group and Stem Cells and Cancer Group - Blood and Bone Diseases Program, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Brisbane, Australia.
authors.forename: Valerie
authors.initials: V
authors.lastname: Barbier
authors.affiliation: Regenerative Medicine Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4049, Brisbane, Australia.
authors.forename: Laure
authors.initials: L
authors.lastname: Thibaudeau
authors.affiliation: Regenerative Medicine Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4049, Brisbane, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Theodoropoulos
authors.affiliation: Australian Prostate Cancer Research Centre Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Brisbane, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Hooper
authors.affiliation: Regenerative Medicine Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4049, Brisbane, Australia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Loessner
authors.affiliation: Australian Prostate Cancer Research Centre Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Brisbane, Australia.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Clements
authors.affiliation: Australian Prostate Cancer Research Centre Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Brisbane, Australia; Cells and Tissue Domain, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4049, Brisbane, Australia.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Russell
authors.affiliation: Bones and Immunology Group - Blood and Bone Diseases Program, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Brisbane, Australia.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Pettit
authors.affiliation: Stem Cell Biology Group and Stem Cells and Cancer Group - Blood and Bone Diseases Program, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Brisbane, Australia.
authors.forename: Ingrid G
authors.initials: IG
authors.lastname: Winkler
authors.affiliation: Stem Cell Biology Group and Stem Cells and Cancer Group - Blood and Bone Diseases Program, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Brisbane, Australia; School of Medicine, The University of Queensland, 288 Herston Road, Herston, QLD 4006, Brisbane, Australia. Electronic address: jp.levesque@mater.uq.edu.au.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Levesque
mesh_terms: D000818:Animals; D021522:Bioartificial Organs; D001846:Bone Development / Q000502:physiology*; D018786:Bone Substitutes / Q000138:chemical synthesis; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004867:Equipment Design; D019544:Equipment Failure Analysis; D005260:Female; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology* / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology; D055153:Stem Cell Niche / Q000502:physiology; D023822:Tissue Engineering / Q000295:instrumentation / Q000379:methods; D054457:Tissue Scaffolds
chemical_list: D018786:Bone Substitutes
keywords: Bone organ; Engraftment; Hematopoietic stem cells; Humanized niche; Tissue Engineering; Transplantation