Bioinspired seeding of biomaterials using three dimensional microtissues induces chondrogenic stem cell differentiation and cartilage formation under growth factor free conditions.
Cell laden biomaterials are archetypically seeded with individual cells and steered into the desired behavior using exogenous stimuli to control growth and differentiation. In contrast, direct cell-cell contact is instructive and even essential for natural tissue formation. Namely, microaggregation and condensation of mesenchymal progenitor cells triggers chondrogenesis and thereby drives limb formation. Yet a biomimetic strategy translating this approach into a cell laden biomaterial-based therapy has remained largely unexplored. Here, we integrate the microenvironment of cellular condensation into biomaterials by encapsulating microaggregates of a hundred human periosteum-derived stem cells. This resulted in decreased stemness-related markers, up regulation of chondrogenic genes and improved in vivo cartilage tissue formation, as compared to single cell seeded biomaterials. Importantly, even in the absence of exogenous growth factors, the microaggregate laden hydrogels outperformed conventional single cell laden hydrogels containing supraphysiological levels of the chondrogenic growth factor TGFB. Overall, the bioinspired seeding strategy described herein represents an efficient and growth factor-free approach to efficiently steer cell fate and drive tissue formation for biomaterial-based tissue engineering strategies.
Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.|Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.|Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
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Leijten
Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.|Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
L S Moreira
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Teixeira
Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.|Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
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Bolander
Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.|Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
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Ji
BIOSYST-MeBioS, Department of Chemistry, KU Leuven, Leuven, Belgium.
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Vanspauwen
BIOSYST-MeBioS, Department of Chemistry, KU Leuven, Leuven, Belgium.
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Lammertyn
Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.|Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
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Schrooten
Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.|Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
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Luyten
D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D032701:Biomimetics / Q000379:methods*; D002356:Cartilage / Q000187:drug effects / Q000254:growth & development*; D002449:Cell Aggregation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D020219:Chondrogenesis / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D051379:Mice; D010521:Periosteum / Q000166:cytology; D021381:Protein Transport / Q000187:drug effects; D055758:SOX9 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D023822:Tissue Engineering / Q000379:methods*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D001672:Biocompatible Materials; D015415:Biomarkers; D036341:Intercellular Signaling Peptides and Proteins; D055758:SOX9 Transcription Factor; D016212:Transforming Growth Factor beta