title: Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate.
abstract: Actively steering the chondrogenic differentiation of mesenchymal stromal cells (MSCs) into either permanent cartilage or hypertrophic cartilage destined to be replaced by bone has not yet been possible. During limb development, the developing long bone is exposed to a concentration gradient of oxygen, with lower oxygen tension in the region destined to become articular cartilage and higher oxygen tension in transient hypertrophic cartilage. Here, we prove that metabolic programming of MSCs by oxygen tension directs chondrogenesis into either permanent or transient hyaline cartilage. Human MSCs chondrogenically differentiated in vitro under hypoxia (2.5% O2) produced more hyaline cartilage, which expressed typical articular cartilage biomarkers, including established inhibitors of hypertrophic differentiation. In contrast, normoxia (21% O2) prevented the expression of these inhibitors and was associated with increased hypertrophic differentiation. Interestingly, gene network analysis revealed that oxygen tension resulted in metabolic programming of the MSCs directing chondrogenesis into articular- or epiphyseal cartilage-like tissue. This differentiation program resembled the embryological development of these distinct types of hyaline cartilage. Remarkably, the distinct cartilage phenotypes were preserved upon implantation in mice. Hypoxia-preconditioned implants remained cartilaginous, whereas normoxia-preconditioned implants readily underwent calcification, vascular invasion, and subsequent endochondral ossification. In conclusion, metabolic programming of MSCs by oxygen tension provides a simple yet effective mechanism by which to direct the chondrogenic differentiation program into either permanent articular-like cartilage or hypertrophic cartilage that is destined to become endochondral bone.
authors.affiliation: MIRA Institute for Biomedical Technology and Technical Medicine, and Departments of Developmental Bioengineering and h.b.j.karperien@utwente.nl.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Leijten
authors.affiliation: MIRA Institute for Biomedical Technology and Technical Medicine, and Departments of Developmental Bioengineering and.
authors.forename: Nicole
authors.initials: N
authors.lastname: Georgi
authors.affiliation: MIRA Institute for Biomedical Technology and Technical Medicine, and Departments of Developmental Bioengineering and.
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreira Teixeira
authors.affiliation: MIRA Institute for Biomedical Technology and Technical Medicine, and Tissue Regeneration, University of Twente, 7522 NB, Enschede, The Netherlands.
authors.forename: Clemens A
authors.initials: CA
authors.lastname: van Blitterswijk
authors.affiliation: MIRA Institute for Biomedical Technology and Technical Medicine, and Departments of Developmental Bioengineering and.
authors.forename: Janine N
authors.initials: JN
authors.lastname: Post
authors.affiliation: MIRA Institute for Biomedical Technology and Technical Medicine, and Departments of Developmental Bioengineering and h.b.j.karperien@utwente.nl.
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002478:Cells, Cultured; D020219:Chondrogenesis; D006801:Humans; D051457:Hyaline Cartilage / Q000166:cytology / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010100:Oxygen / Q000378:metabolism*
chemical_list: D010100:Oxygen
keywords: cell therapy; chondral defects; regenerative medicine; skeletogenesis; tissue engineering