Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment
Summary: Human mesenchymal stem cells (MSCs) remain one of the best cell sources for cartilage, a tissue without regenerative capacity. However, MSC chondrogenesis is commonly induced through TGFβ, a pleomorphic growth factor without specificity for this lineage. Using tissue- and induced pluripoten...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222019861 |
| _version_ | 1797946164969996288 |
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| author | Chen-Chan Hsieh B. Linju Yen Chia-Chi Chang Pei-Ju Hsu Yu-Wei Lee Men-Luh Yen Shaw-Fang Yet Linyi Chen |
| author_facet | Chen-Chan Hsieh B. Linju Yen Chia-Chi Chang Pei-Ju Hsu Yu-Wei Lee Men-Luh Yen Shaw-Fang Yet Linyi Chen |
| author_sort | Chen-Chan Hsieh |
| collection | DOAJ |
| description | Summary: Human mesenchymal stem cells (MSCs) remain one of the best cell sources for cartilage, a tissue without regenerative capacity. However, MSC chondrogenesis is commonly induced through TGFβ, a pleomorphic growth factor without specificity for this lineage. Using tissue- and induced pluripotent stem cell-derived MSCs, we demonstrate an efficient and precise approach to induce chondrogenesis through Wnt/β-catenin antagonism alone without TGFβ. Compared to TGFβ, Wnt/β-catenin antagonism more rapidly induced MSC chondrogenesis without eliciting off-target lineage specification toward smooth muscle or hypertrophy; this was mediated through increasing N-cadherin levels and β-catenin interactions—key components of the adherens junctions (AJ)—and increasing cytoskeleton-mediated condensation. Validation with transcriptomic analysis of human chondrocytes compared to MSCs and osteoblasts showed significant downregulation of Wnt/β-catenin and TGFβ signaling along with upregulation of α-catenin as an upstream regulator. Our findings underscore the importance of understanding developmental pathways and structural modifications in achieving efficient MSC chondrogenesis for translational application. |
| first_indexed | 2024-04-10T21:06:33Z |
| format | Article |
| id | doaj.art-72d493f3ddab43c0b52107c7110b4854 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-10T21:06:33Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-72d493f3ddab43c0b52107c7110b48542023-01-22T04:40:30ZengElsevieriScience2589-00422023-01-01261105713Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitmentChen-Chan Hsieh0B. Linju Yen1Chia-Chi Chang2Pei-Ju Hsu3Yu-Wei Lee4Men-Luh Yen5Shaw-Fang Yet6Linyi Chen7Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan; Regenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, Miaoli County35053, TaiwanRegenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, Miaoli County35053, Taiwan; Corresponding authorRegenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, Miaoli County35053, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center (NDMC), Taipei, TaiwanRegenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, Miaoli County35053, TaiwanRegenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, Miaoli County35053, TaiwanDepartment of Obstetrics/Gynecology, National Taiwan University (NTU) Hospital and College of Medicine, NTU, Taipei, TaiwanRegenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, Miaoli County35053, TaiwanInstitute of Molecular Medicine, National Tsing Hua University, Hsinchu, TaiwanSummary: Human mesenchymal stem cells (MSCs) remain one of the best cell sources for cartilage, a tissue without regenerative capacity. However, MSC chondrogenesis is commonly induced through TGFβ, a pleomorphic growth factor without specificity for this lineage. Using tissue- and induced pluripotent stem cell-derived MSCs, we demonstrate an efficient and precise approach to induce chondrogenesis through Wnt/β-catenin antagonism alone without TGFβ. Compared to TGFβ, Wnt/β-catenin antagonism more rapidly induced MSC chondrogenesis without eliciting off-target lineage specification toward smooth muscle or hypertrophy; this was mediated through increasing N-cadherin levels and β-catenin interactions—key components of the adherens junctions (AJ)—and increasing cytoskeleton-mediated condensation. Validation with transcriptomic analysis of human chondrocytes compared to MSCs and osteoblasts showed significant downregulation of Wnt/β-catenin and TGFβ signaling along with upregulation of α-catenin as an upstream regulator. Our findings underscore the importance of understanding developmental pathways and structural modifications in achieving efficient MSC chondrogenesis for translational application.http://www.sciencedirect.com/science/article/pii/S2589004222019861BioengineeringBiological sciencesMolecular medicineTissue engineering |
| spellingShingle | Chen-Chan Hsieh B. Linju Yen Chia-Chi Chang Pei-Ju Hsu Yu-Wei Lee Men-Luh Yen Shaw-Fang Yet Linyi Chen Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment iScience Bioengineering Biological sciences Molecular medicine Tissue engineering |
| title | Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment |
| title_full | Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment |
| title_fullStr | Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment |
| title_full_unstemmed | Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment |
| title_short | Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment |
| title_sort | wnt antagonism without tgfβ induces rapid msc chondrogenesis via increasing aj interactions and restricting lineage commitment |
| topic | Bioengineering Biological sciences Molecular medicine Tissue engineering |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222019861 |
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