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Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs
Zixuan Lin1,2, Zhong Li1, Eileen N Li1,3
1Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Abstract:
Osteoarthritis (OA) is a chronic disease mainly characterized by degenerative changes in cartilage, but other joint elements such as bone are also affected. To date, there are no disease-modifying OA drugs (DMOADs), owing in part to a deficiency of current models in simulating OA pathologies and etiologies in humans. In this study, we aimed to develop microphysiological osteochondral (OC) tissue chips derived from human induced pluripotent stem cells (iPSCs) to model the pathologies of OA. We first induced iPSCs into mesenchymal progenitor cells (iMPCs) and optimized the chondro- and osteo-inductive conditions for iMPCs. Then iMPCs were encapsulated into photocrosslinked gelatin scaffolds and cultured within a dual-flow bioreactor, in which the top stream was chondrogenic medium and the bottom stream was osteogenic medium. After 28 days of differentiation, OC tissue chips were successfully generated and phenotypes were confirmed by real time RT-PCR and histology. To create an OA model, interleukin-1β (IL-1β) was used to challenge the cartilage component for 7 days. While under control conditions, the bone tissue promoted chondrogenesis and suppressed chondrocyte terminal differentiation of the overlying chondral tissue. Under conditions modeling OA, the bone tissue accelerated the degradation of chondral tissue which is likely via the production of catabolic and inflammatory cytokines. These findings suggest active functional crosstalk between the bone and cartilage tissue components in the OC tissue chip under both normal and pathologic conditions. Finally, a selective COX-2 inhibitor commonly prescribed drug for OA, Celecoxib, was shown to downregulate the expression of catabolic and proinflammatory cytokines in the OA model, demonstrating the utility of the OC tissue chip model for drug screening. In summary, the iPSC-derived OC tissue chip developed in this study represents a high-throughput platform applicable for modeling OA and for the screening and testing of candidate DMOADs.
Insights
This study developed a human osteochondral tissue chip from stem cells to model osteoarthritis (OA). The model successfully replicated OA pathologies and demonstrated potential for screening new osteoarthritis drugs.
Area of Science:
- Biotechnology and Regenerative Medicine
- Stem Cell Biology
- Biomaterials Engineering
Background:
- Osteoarthritis (OA) is a degenerative joint disease affecting cartilage and bone, with no current disease-modifying drugs.
- Existing OA models lack the complexity to fully replicate human disease pathologies and etiologies.
- Microphysiological systems offer potential for more accurate disease modeling.
Purpose of the Study:
- To develop a microphysiological osteochondral (OC) tissue chip using human induced pluripotent stem cells (iPSCs).
- To model human osteoarthritis (OA) pathologies and enable drug screening.
- To investigate the functional crosstalk between bone and cartilage in normal and OA conditions.
Main Methods:
- Induced pluripotent stem cells (iPSCs) were differentiated into mesenchymal progenitor cells (iMPCs).
- iMPCs were encapsulated in gelatin scaffolds and cultured in a dual-flow bioreactor with distinct chondrogenic and osteogenic media.
- Osteoarthritis (OA) was induced using interleukin-1β (IL-1β), and the efficacy of Celecoxib was tested.
Main Results:
- Successfully generated human iPSC-derived osteochondral (OC) tissue chips.
- Demonstrated functional crosstalk between bone and cartilage, with bone accelerating cartilage degradation under OA conditions.
- The OA model showed reduced catabolic and proinflammatory cytokines upon treatment with Celecoxib, a COX-2 inhibitor.
Conclusions:
- The iPSC-derived OC tissue chip is a viable platform for modeling OA.
- This model highlights the active role of bone in OA pathogenesis and cartilage degradation.
- The platform demonstrates utility for high-throughput screening of potential disease-modifying osteoarthritis drugs (DMOADs).
