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 TGF beta, 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/beta-catenin antagonism alone without TGF beta. Compared to TGF beta, Wnt/beta-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 beta-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/beta-catenin and TGF beta signaling along with upregulation of alpha-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.
Date:
2023-01-20
Relation:
iScience. 2023 Jan 20;26(1):Article number 105713.
