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Engineering osteoarthritic cartilage model through differentiating senescent human mesenchymal stem cells for testing disease-modifying drugs

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Abstract

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis (OA). In this study, we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs (DMOADs). Specifically, human bone marrow-derived mesenchymal stromal cells (MSCs) were expanded in vitro up to passage 10 (P10-MSCs). Following their senescent phenotype formation, P10-MSCs were subjected to pellet culture in chondrogenic medium. Results from qRT-PCR, histology, and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents, when compared to that from normal passage 4 (P4)-MSCs. Interestingly, the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples, as demonstrated by RNA Sequencing data and other analysis methods. Lastly, the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics. The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage. The P4- and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.

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Acknowledgements

This work was supported by Department of Orthopaedic Surgery at the University of Pittsburgh and the Albert B. Ferguson, Jr., M.D. Orthopaedic Fund of The Pittsburgh Foundation. Ning Wang is a medical student at the University of Pittsburgh School of Medicine supported by the Central South University Xiangya School of Medicine.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA

    Ning Wang, Yuchen He, Meagan J. Makarcyzk, Peter G. Alexander, Tingjun Hao, Anne-Marie Padget & Hang Lin

  2. Department of Orthopedic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China

    Ning Wang, Yuchen He & Guanghua Lei

  3. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA

    Silvia Liu

  4. Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA, 15219, USA

    Meagan J. Makarcyzk & Hang Lin

  5. Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA

    Alexander Chang

  6. McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA

    Peter G. Alexander & Hang Lin

  7. Department of Biology, University of Pittsburgh Dietrich School of Arts and Science, Pittsburgh, PA, 15219, USA

    Anne-Marie Padget

  8. Department of Research B2B, Life Length SL, Madrid, 28010, Spain

    Nuria de Pedro & Tsapekos Menelaos

  9. Xiangya Third Hospital, Central South University, Changsha, 410013, China

    Ning Wang

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  1. Ning Wang
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Correspondence to Hang Lin.

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Compliance and ethics The author(s) declare that they have no conflict of interest. Life Length SL did not provide any financial support and did not influence the results reported in this study. With the approval from the Institutional Review Boards (University of Pittsburgh and University of Washington), the cartilage tissues and bone marrows were collected from the patients who underwent total knee joint replacement, which were used to isolate chondrocytes and mesenchymal stem cells, respectively.

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Engineering Osteoarthritic Cartilage Model through Differentiating Senescent Human Mesenchymal Stem Cells for Testing Disease-Modifying Drugs

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Wang, N., He, Y., Liu, S. et al. Engineering osteoarthritic cartilage model through differentiating senescent human mesenchymal stem cells for testing disease-modifying drugs. Sci. China Life Sci. 65, 309–327 (2022). https://doi.org/10.1007/s11427-021-1933-7

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