Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment

Chen-Chan Hsieh; B Linju Yen; Chia-Chi Chang; Pei-Ju Hsu; Yu-Wei Lee; Men-Luh Yen; Shaw-Fang Yet; Linyi Chen

doi:10.1016/j.isci.2022.105713

Wnt antagonism without TGFβ induces rapid MSC chondrogenesis via increasing AJ interactions and restricting lineage commitment

iScience. 2022 Dec 2;26(1):105713. doi: 10.1016/j.isci.2022.105713. eCollection 2023 Jan 20.

Authors

Chen-Chan Hsieh^{1

2}, B Linju Yen², Chia-Chi Chang^{2

3}, Pei-Ju Hsu², Yu-Wei Lee², Men-Luh Yen⁴, Shaw-Fang Yet², Linyi Chen¹

Affiliations

¹ Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.
² Regenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), 35 Keyan Road, Zhunan, Miaoli County35053, Taiwan.
³ Graduate Institute of Life Sciences, National Defense Medical Center (NDMC), Taipei, Taiwan.
⁴ Department of Obstetrics/Gynecology, National Taiwan University (NTU) Hospital and College of Medicine, NTU, Taipei, Taiwan.

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.

Keywords: Bioengineering; Biological sciences; Molecular medicine; Tissue engineering.