Human pluripotent stem cell-derived cartilaginous organoids promote scaffold-free healing of critical size long bone defects

Tam, Wai Long; Freitas Mendes, Luís; Chen, Xike; Lesage, Raphaëlle; Van Hoven, Inge; Leysen, Elke; Kerckhofs, Greet; Bosmans, Kathleen; Chai, Yoke Chin; Yamashita, Akihiro; Tsumaki, Noriyuki; Geris, Liesbet; Roberts, Scott J.; Luyten, Frank P.

Abstract

Background
Bones have a remarkable capacity to heal upon fracture. Yet, in large defects or compromised conditions healing processes become impaired, resulting in delayed or non-union. Current therapeutic approaches often utilize autologous or allogeneic bone grafts for bone augmentation. However, limited availability of these tissues and lack of predictive biological response result in limitations for clinical demands. Tissue engineering using viable cell-based implants is a strategic approach to address these unmet medical needs.

Methods
Herein, the in vitro and in vivo cartilage and bone tissue formation potencies of human pluripotent stem cells were investigated. The induced pluripotent stem cells were specified towards the mesodermal lineage and differentiated towards chondrocytes, which subsequently self-assembled into cartilaginous organoids. The tissue formation capacity of these organoids was then challenged in an ectopic and orthotopic bone formation model.

Results
The derived chondrocytes expressed similar levels of collagen type II as primary human articular chondrocytes and produced stable cartilage when implanted ectopically in vivo. Upon targeted promotion towards hypertrophy and priming with a proinflammatory mediator, the organoids mediated successful bridging of critical size long bone defects in immunocompromised mice.

Conclusions
These results highlight the promise of induced pluripotent stem cell technology for the creation of functional cartilage tissue intermediates that can be explored for novel bone healing strategies.

Citation

Tam, W. L., Freitas Mendes, L., Chen, X., Lesage, R., Van Hoven, I., Leysen, E., …Luyten, F. P. (2021). Human pluripotent stem cell-derived cartilaginous organoids promote scaffold-free healing of critical size long bone defects. Stem Cell Research and Therapy, 12(1), https://doi.org/10.1186/s13287-021-02580-7

• Journal Article Type: Article
• Acceptance Date: Aug 20, 2021
• Online Publication Date: Sep 25, 2021
• Publication Date: Sep 25, 2021
• Deposit Date: Oct 4, 2021
• Publicly Available Date: Oct 4, 2021
• Journal: Stem Cell Research & Therapy
• Publisher: BioMed Central
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 1
• DOI: https://doi.org/10.1186/s13287-021-02580-7
• Keywords: Cell Biology; Biochemistry, Genetics and Molecular Biology (miscellaneous); Molecular Medicine; Medicine (miscellaneous)
• Public URL: https://rvc-repository.worktribe.com/output/1551452
• Additional Information: Received: 12 March 2021; Accepted: 20 August 2021; First Online: 25 September 2021; : ; : Informed consent has been obtained from the donor of the embryo/tissue from which the pluripotent stem cells have been derived. The animal experimental procedures were approved by the local ethical committee for animal research (KU Leuven). The animals were housed according to the guidelines provided by the Animalium Leuven (KU Leuven).; : Not applicable.; : The authors declare that they have no competing interests.