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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Bibliographic Details
Main Authors: Chen-Chan Hsieh, B. Linju Yen, Chia-Chi Chang, Pei-Ju Hsu, Yu-Wei Lee, Men-Luh Yen, Shaw-Fang Yet, Linyi Chen
Format: Article
Language:English
Published: Elsevier 2023-01-01
Series:iScience
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Online Access:http://www.sciencedirect.com/science/article/pii/S2589004222019861
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Summary: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.
ISSN:2589-0042