Differential effects of equiaxial and uniaxial strain on mesenchymal stem cells

Abstract

Bone marrow mesenchymal stem cells (MSCs) can differentiate into a variety of cell types, including vascular smooth muscle cells (SMCs), and have tremendous potential as a cell source for cardiovascular regeneration. We postulate that specific vascular environmental factors will promote MSC differentiation into SMCs. However, the effects of the vascular mechanical environment on MSCs have not been characterized. Here we show that mechanical strain regulated the expression of SMC markers in MSCs. Cyclic equiaxial strain downregulated SM alpha-actin and SM-22alpha in MSCs on collagen- or elastin-coated membranes after 1 day, and decreased alpha-actin in stress fibers. In contrast, cyclic uniaxial strain transiently increased the expression of SM alpha-actin and SM-22alpha after 1 day, which subsequently returned to basal levels after the cells aligned in the direction perpendicular to the strain direction. In addition, uniaxial but not equiaxial strain induced a transient increase of collagen I expression. DNA microarray experiments showed that uniaxial strain increased SMC markers and regulated the expression of matrix molecules without significantly changing the expression of the differentiation markers (e.g., alkaline phosphatase and collagen II) of other cell types. Our results suggest that uniaxial strain, which better mimics the type of mechanical strain experienced by SMCs, may promote MSC differentiation into SMCs if cell orientation can be controlled. This study demonstrates the differential effects of equiaxial and uniaxial strain, advances our understanding of the mechanical regulation of stem cells, and provides a rational basis for engineering MSCs for vascular tissue engineering and regeneration.

Anisotropic mechanosensing by mesenchymal stem cells

“…Previous work has shown that mechanical strain has an effect on proliferation and differentiation of vascular SMCs, including up-regulation of various SMC contractile markers (8)(9)(10), and the cells aligned perpendicularly to the axis of strain (11). Similarly, we have shown that when MSCs are subjected to conditions of cyclic uniaxial strain on silicone membranes, the cells show an initial up-regulation of SMC markers that eventually drops back to basal levels after the cells align perpendicularly to the axis of strain as a means of reducing the effective stress on their cytoskeleton (12). This cellular orientation differs from in vivo conditions where vascular SMCs align in the circumferential direction (13,14) or, in some cases, in a helical pattern (15) in the arterial wall and SMCs are subject to circumferential cyclic strain because of the pulsatile nature of the blood pressure.…”

“…Several studies have shown that SMC response to this stimulus involves up-regulation of smooth muscle markers such as h-caldesmon (8), SM-1͞2 (24), and SM ␣-actin (9). However, our previous study revealed a decrease in the smooth muscle markers SM ␣-actin and SM22 when MSCs were stimulated with cyclic equiaxial strain (12).…”

“…However, when MSCs are stimulated with cyclic uniaxial strain on unpatterned silicone membranes, the cells aligned in the perpendicular direction, which affected the stress applied to the cells and thus the cell responses (12,23). In this study, we have shown that micropatterning techniques can be used to keep MSCs aligned with the axis of strain and simulate the guidance of cells by matrix fibrils.…”

Response of mesenchymal stem cells to shear stress in tissue-engineered vascular grafts

“…O'Cearbhaill et al [29] did not observe vWF expression on the protein level under static or mechanically stimulated conditions, nor did they observe a significant change in vWF at the mRNA level. The combined effect of radial stress and hoop stress used in the experiment may have surpassed the effect of shear stress in cell differentiation, because cyclic stress promotes the expression of smooth muscle-like properties [10,30,31] . Because MSCs can also differentiate along SMC lines, we hypothesized that differentiation along the endothelial line might accompany shear stress-induced negative regula- tion of the expression of SMC-related markers, such as SM α-actin and calponin.…”

Review:Ex VivoEngineering of Living Tissues with Adult Stem Cells

“…Uniaxial stretching transiently enhances the expression of smooth muscle markers like smooth muscle a-actin in human BMSCs, whereas equilateral stretching inhibits smooth muscle differentiation. 111 …”