Human Mesenchymal Stem Cells Form Multicellular Structures in Response to Applied Cyclic Strain

Abstract

Mesenchymal stem cells (MSCs) are a component of many cardiovascular cell-based regenerative medicine therapies. There is little understanding, however, of the response of MSCs to mechanical cues present in cardiovascular tissues. The objectives of these studies were to identify a model system to study the effect of well-defined applied cyclic strain on MSCs and to use this system to determine the effect of cyclic equibiaxial strain on the cellular and cytoskeletal organization of MSCs. When exposed to 10%, 1 Hz cyclic equibiaxial strain for 48 h, MSCs remained viable, retained characteristic gene and protein markers, and rearranged to form multicellular structures defined as clusters and knobs. This novel observation of cluster (overlapping cells surrounded by radial cellular projections) and knob (more dome-like structure containing significantly more cells than a cluster) formation did not involve changes in cytoskeletal proteins and resulted from cellular rearrangements initiated within 8 h of applied strain. Observed cellular responses were found to be dependent on substrate coating, but not on cell density for the 8-fold ranges tested. This system can thus be used to study the mechanoresponse over hours to days of MSCs exposed to applied cyclic strain in the context of cell-cell and cell-matrix interactions.

Mesenchymal Stem Cell Mechanobiology

“…MSCs exposed to cyclic equibiaxial strain exhibit increased mineralized matrix production and upregulation of osteogenic genes. In addition, MSCs exposed to tensile strain undergo spatial rearrangement to form clusters and knob-like three-dimensional (3-D) structures [35], suggesting that mechanical signals may influence cellular migration. Tensile strain has also been shown to inhibit adipogenesis [33], suggesting that specific mechanical cues may serve as a switch between osteogenesis and other mesenchymal lineages.…”

Differentiation Patterns of Embryonic Stem Cells in Two- versus Three-Dimensional Culture

“…The common configurations of cells on a monolayer (refs for 2D differentiation), embedded in protein gels [Bosnakovski et al, 2006; Gerecht et al, 2007] and in suspension [Itskovitz-Eldor et al, 2000; Dang et al, 2002] have both advantages and disadvantages. Stem cells cultured on adherent surfaces can be presented with bound proteins [Nishikawa et al, 1998; Schenke-Layland et al, 2007] and well-controlled exogenous physical cues, such as cyclic tension [Saha et al, 2006; Doyle et al, 2009] and shear stress [Ahsan and Nerem, 2010; Nikmanesh et al, 2012; Wolfe et al, 2012]. Yet, culture in this 2D configuration restricts cell growth to a single geometric plane.…”

Nanomechanics to Drive Stem Cells in Injured Tissues: Insights from Current Research and Future Perspectives

“…In that case, the mechanical stimulation of MSCs increased also their paracrine proangiogenic properties, such as the release of fibroblast growth factor and vascular endothelial growth factor [37]. The mechanical force affects, at a transcriptional level, the proliferation, differentiation, and migration of MSCs by modifying their physical perception of the environment [4] and allowing the alignment of stem cells perpendicularly to the axis of strain [32], as previously demonstrated in differentiated cells involved in tissue remodeling, such as endothelial cells, myocytes [38], and fibroblasts [39].…”

“…Although it is widely accepted that different physical forces (i.e., stretch, strain, tension, and compression) are involved in mature tissue remodeling, the role played by mechanical loading in the differentiation, maturation, and migration of stem cells during tissue repair=regeneration has begun to attract increased attention from several researchers. Recent studies showed that specific in vitro mechanical signals, in specially designed bioreactors, provide important adjuncts to biochemical signaling pathways for promoting engineered tissue growth [4]. Increasing evidence suggests that the mechanosensing apparatus of a stem cell is different from that of differentiated cells [5].…”