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The mechanical properties of the local microenvironment may have important influence on the fate and function of adult tissue progenitor cells, altering the regenerative process. This is particularly critical following a myocardial infarction, in which the normal, compliant myocardial tissue is replaced with fibrotic, stiff scar tissue. In this study, we examined the effects of matrix stiffness on adult cardiac side population (CSP) progenitor cell behavior. Ovine and murine CSP cells were isolated and cultured on polydimethylsiloxane substrates, replicating the elastic moduli of normal and fibrotic myocardium. Proliferation capacity and cell cycling were increased in CSP cells cultured on the stiff substrate with an associated reduction in cardiomyogeneic differentiation and accelerated cell ageing. In addition, culture on stiff substrate stimulated upregulation of extracellular matrix and adhesion proteins gene expression in CSP cells. Collectively, we demonstrate that microenvironment properties, including matrix stiffness, play a critical role in regulating progenitor cell functions of endogenous resident CSP cells. Understanding the effects of the tissue microenvironment on resident cardiac progenitor cells is a critical step toward achieving functional cardiac regeneration.

Polydimethylsiloxane (PDMS)-based micropillars (or microcantilevers) have been used as bio-transducers for measuring cellular forces on the order of pN to μN. The measurement accuracy of these sensitive devices depends on appropriate modeling to convert the micropillar deformations into the corresponding reaction forces. The traditional approach to calculating the reaction force is based on the Euler beam theory with consideration of a linear elastic slender beam for the micropillar. However, the low aspect ratio in geometry of PDMS micropillars does not satisfy the slender beam requirement. Consequently, the Timoshenko beam theory, appropriate for a beam with a low aspect ratio, should be used. In addition, the inherently time-dependent behavior in PDMS has to be considered for accurate force conversion. In this paper, the Timoshenko beam theory, along with the consideration of viscoelastic behavior of PDMS, was used to model the mechanical response of micropillars. The viscoelastic behavior of PDMS was characterized by stress relaxation nanoindentation using a circular flat punch. A correction procedure was developed to determine the load-displacement relationship with consideration of ramp loading. The relaxation function was extracted and described by a generalized Maxwell model. The bending of rectangular micropillars was performed by a wedge indenter tip. The viscoelastic Timoshenko beam formula was used to calculate the mechanical response of the micropillar, and the results were compared with measurement data. The calculated reaction forces agreed well with the experimental data at three different loading rates. A parametric study was conducted to evaluate the accuracy of the viscoelastic Timoshenko beam model by comparing the reaction forces calculated from the elastic Euler beam, elastic Timoshenko beam and viscoelastic Euler beam models at various aspect ratios and loading rates. The extension of modeling from the elastic Euler beam theory to the viscoelastic Timoshenko beam theory has improved the accuracy for the conversion of the PDMS micropillar deformations to forces, which will benefit the polymer-based micro bio-transducer applications.

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