Combinatorial screening of biochemical and physical signals for phenotypic regulation of stem cell–based cartilage tissue engineering

Abstract

Despite great progress in biomaterial design strategies for replacing damaged articular cartilage, prevention of stem cell-derived chondrocyte hypertrophy and resulting inferior tissue formation is still a critical challenge. Here, by using engineered biomaterials and a high-throughput system for screening of combinatorial cues in cartilage microenvironments, we demonstrate that biomaterial cross-linking density that regulates matrix degradation and stiffness—together with defined presentation of growth factors, mechanical stimulation, and arginine-glycine-aspartic acid (RGD) peptides—can guide human mesenchymal stem cell (hMSC) differentiation into articular or hypertrophic cartilage phenotypes. Faster-degrading, soft matrices promoted articular cartilage tissue formation of hMSCs by inducing their proliferation and maturation, while slower-degrading, stiff matrices promoted cells to differentiate into hypertrophic chondrocytes through Yes-associated protein (YAP)–dependent mechanotransduction. in vitro and in vivo chondrogenesis studies also suggest that down-regulation of the Wingless and INT-1 (WNT) signaling pathway is required for better quality articular cartilage-like tissue production.

Marginal sealing around integral bilayer scaffolds for repairing osteochondral defects based on photocurable silk hydrogels

“…Immunofluorescence staining of Sox9 showed that the 10–20% D/S group had higher expression than the 30% D/S group ( Appendix A , Appendix A ). These results suggested that 30% D/S group with excessive stiffness and smooth surface is unsuitable for chondrocyte growth and chondrogenesis [ 35 , 36 ]. On the other hand, almost all BMSCs were alive on the P/S materials, verifying the excellent biocompatibility of this scaffold ( Fig.…”

The hypertrophic cartilage induction influences the building‐block capacity of human adipose stem/stromal cell spheroids for biofabrication

“…Some recent studies exploring the relationship between biomechanical properties and hypertrophy in cell culture models have already been published. 50,51 These studies, however, were not performed with a hypertrophic model based on spheroids to understand how the biomechanical properties of hypertrophic induced spheroids can influence their buildingblock capacity for bioassembly approaches.…”

Role of Canonical Wnt/β-Catenin Pathway in Regulating Chondrocytic Hypertrophy in Mesenchymal Stem Cell-Based Cartilage Tissue Engineering

“…Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) signaling are important in the development of cartilage ( Vanyai et al, 2020 ). Specifically, low level of yes-associated protein (YAP), a transcription factor of the Hippo pathway, was associated with the formation of articular cartilage from MSCs ( Lee et al, 2020 ). Using murine models, Deng et al demonstrated that Yap1 overexpression significantly reduced COL10A1 level, which however was at the expense of reduced chondrogenesis.…”

“…Recently, mechanical loading, under certain conditions, was shown to suppress hypertrophy ( Aisenbrey et al, 2019 ). In the study by Lee et al, MSCs cultured in 3D chondrogenic combinatorial system with 40% strain showed a trend toward hypertrophic chondrocytes, indicated by the high level of RUNX2, which was also accompanied with more YAP expression ( Lee et al, 2020 ). Of note, the association between mechanical loading and Wnt/β-catenin has been previously demonstrated ( Sen et al, 2011 ; He et al, 2020 ).…”