Abstract
Since material stiffness controls many cell functions, we reviewed the currently available knowledge on stiffness sensing and elucidated what is known in the context of clinical and experimental articular cartilage (AC) repair. Remarkably, no stiffness information on the various biomaterials for clinical AC repair was accessible. Using mRNA expression profiles and morphology as surrogate markers of stiffness-related effects, we deduced that the various clinically available biomaterials control chondrocyte (CH) phenotype well, but not to equal extents, and only in non-degenerative settings. Ample evidence demonstrates that multiple molecular aspects of CH and mesenchymal stromal cell (MSC) phenotype are susceptible to material stiffness, because proliferation, migration, lineage determination, shape, cytoskeletal properties, expression profiles, cell surface receptor composition, integrin subunit expression, and nuclear shape and composition of CHs and/or MSCs are stiffness-regulated. Moreover, material stiffness modulates MSC immuno-modulatory and angiogenic properties, transforming growth factor beta 1 (TGF-β1)-induced lineage determination, and CH re-differentiation/de-differentiation, collagen type II fragment production, and TGF-β1- and interleukin 1 beta (IL-1β)-induced changes in cell stiffness and traction force. We then integrated the available molecular signaling data into a stiffness-regulated CH phenotype model. Overall, we recommend using material stiffness for controlling cell phenotype, as this would be a promising design cornerstone for novel future-oriented, cell-instructive biomaterials for clinical high-quality AC repair tissue.
Highlights
Microenvironmental stimuli control cell fate and function [1]
They demonstrated that the expression levels of SRY-related HMG box gene 9 (SOX9), collagen type II, ACAN, and endogenous transforming growth factor β (TGF-β) were highest on 0.5 MPa substrates in murine CHs (mCHs), whereas the response to the chondrogenic growth factor TGF-β measured in ATDC5 cells was higher on 0.5 MPa vs. plastic substrates
The aim of this review was (i) to summarize the current knowledge on how cells perceive and transduce material stiffness, and to answer the question whether the approach to control material stiffness for guiding cell fate is effective in the context of CH phenotype and mesenchymal stromal cell (MSC) differentiation, as those cells remain the most relevant cell types for clinical cartilage repair
Summary
Microenvironmental stimuli control cell fate and function [1]. One of the key biomechanical determinants is the stiffness of the extracellular matrix (ECM) [2,3], which is the scaffolding structure for tissues and organs that embeds the tissue-resident cells. Based on OA-related changes in ECM stiffness, a number of studies have subsequently examined how biomechanical stiffness influences CH morphology and phenotype. Even after a decade of mechanobiological research, it remains poorly understood how OA-associated ECM stiffness changes affect CH phenotype and, alter cell behavior during disease progression. The aim of this review is to summarize how cells and CHs and mesenchymal stem cells (MSCs) sense stiffness, and to answer whether the approach to control material stiffness for controlling cell fate is effective in controlling the phenotype and differentiation of CHs and MSCs, as these are key cells involved in AC repair [30]. This review presents the available data on specific stiffness-related topics in dedicated chapters, whereas the discussion chapter focuses on interpreting these data and assembling a model of the material stiffness-dependency of CH phenotype
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