Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment
Journal
iScience
Journal Volume
26
Journal Issue
1
Date Issued
2023-01-20
Author(s)
Hsieh, Chen-Chan
Yen, B Linju
Chang, Chia-Chi
Hsu, Pei-Ju
Lee, Yu-Wei
Yet, Shaw-Fang
Chen, Linyi
Abstract
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.
Subjects
Bioengineering; Biological sciences; Molecular medicine; Tissue engineering
Publisher
CELL PRESS
Type
journal article