Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs
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 eti...
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Frontiers Media S.A.
2019-12-01
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Series: | Frontiers in Bioengineering and Biotechnology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fbioe.2019.00411/full |
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doaj-9a57735f58854794a6a4ad0eccc38295 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zixuan Lin Zixuan Lin Zhong Li Eileen N. Li Eileen N. Li Xinyu Li Xinyu Li Colin J. Del Duke He Shen Tingjun Hao Tingjun Hao Benjamen O'Donnell Bruce A. Bunnell Stuart B. Goodman Peter G. Alexander Rocky S. Tuan Rocky S. Tuan Rocky S. Tuan Hang Lin Hang Lin Hang Lin |
spellingShingle |
Zixuan Lin Zixuan Lin Zhong Li Eileen N. Li Eileen N. Li Xinyu Li Xinyu Li Colin J. Del Duke He Shen Tingjun Hao Tingjun Hao Benjamen O'Donnell Bruce A. Bunnell Stuart B. Goodman Peter G. Alexander Rocky S. Tuan Rocky S. Tuan Rocky S. Tuan Hang Lin Hang Lin Hang Lin Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs Frontiers in Bioengineering and Biotechnology iPSCs DMOADs tissue chip osteoarthritis Celecoxib |
author_facet |
Zixuan Lin Zixuan Lin Zhong Li Eileen N. Li Eileen N. Li Xinyu Li Xinyu Li Colin J. Del Duke He Shen Tingjun Hao Tingjun Hao Benjamen O'Donnell Bruce A. Bunnell Stuart B. Goodman Peter G. Alexander Rocky S. Tuan Rocky S. Tuan Rocky S. Tuan Hang Lin Hang Lin Hang Lin |
author_sort |
Zixuan Lin |
title |
Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs |
title_short |
Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs |
title_full |
Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs |
title_fullStr |
Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs |
title_full_unstemmed |
Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs |
title_sort |
osteochondral tissue chip derived from ipscs: modeling oa pathologies and testing drugs |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Bioengineering and Biotechnology |
issn |
2296-4185 |
publishDate |
2019-12-01 |
description |
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. |
topic |
iPSCs DMOADs tissue chip osteoarthritis Celecoxib |
url |
https://www.frontiersin.org/article/10.3389/fbioe.2019.00411/full |
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doaj-9a57735f58854794a6a4ad0eccc382952020-11-25T01:01:47ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852019-12-01710.3389/fbioe.2019.00411493543Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing DrugsZixuan Lin0Zixuan Lin1Zhong Li2Eileen N. Li3Eileen N. Li4Xinyu Li5Xinyu Li6Colin J. Del Duke7He Shen8Tingjun Hao9Tingjun Hao10Benjamen O'Donnell11Bruce A. Bunnell12Stuart B. Goodman13Peter G. Alexander14Rocky S. Tuan15Rocky S. Tuan16Rocky S. Tuan17Hang Lin18Hang Lin19Hang Lin20Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesXiangya School of Medicine, Central South University, Changsha, ChinaDepartment of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA, United StatesDepartment of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA, United StatesDepartment of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA, United StatesDepartment of Pharmacology, Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA, United StatesDepartment of Pharmacology, Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA, United StatesDepartment of Orthopaedic Surgery and Bioengineering, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA, United StatesMcGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA, United StatesMcGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesOsteoarthritis (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.https://www.frontiersin.org/article/10.3389/fbioe.2019.00411/fulliPSCsDMOADstissue chiposteoarthritisCelecoxib |