The phenotypic expression and function of stem cells are regulated by their integrated response to variable microenvironmental cues, including growth factors and cytokines, matrix-mediated signals, and cell-cell interactions. Recently, growing evidence suggests that matrix-mediated signals include mechanical stimuli such as strain, shear stress, substrate rigidity and topography, and these stimuli have a more profound impact on stem cell phenotypes than had previously been recognized, e.g. self-renewal and differentiation through the control of gene transcription and signaling pathways. Using a variety of cell culture models enabled by micro and nanoscale technologies, we are beginning to systematically and quantitatively investigate the integrated response of cells to combinations of relevant mechanobiological stimuli. This paper reviews recent advances in engineering physical stimuli for stem cell mechanobiology and discusses how micro-and nanoscale engineered platforms can be used to control stem cell niche environments and regulate stem cell fate and function.

Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). The aim of this open-label phase I clinical trial was to evaluate the safety of two repeated intrathecal injections of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) in ALS patients. Eight patients with definite or probable ALS were enrolled. After a 3-month lead-in period, autologous MSCs were isolated two times from the BM at an interval of 26 days and were then expanded in vitro for 28 days and suspended in autologous cerebrospinal fluid. Of the 8 patients, 7 received 2 intrathecal injections of autologous MSCs (1 3 10 6 cells per kg) 26 days apart. Clinical or laboratory measurements were recorded to evaluate the safety 12 months after the first MSC injection. The ALS Functional Rating Scale-Revised (ALSFRS-R), the Appel ALS score, and forced vital capacity were used to evaluate the patients' disease status. One patient died before treatment and was withdrawn from the study. With the exception of that patient, no serious adverse events were observed during the 12-month follow-up period. Most of the adverse events were self-limited or subsided after supportive treatment within 4 days. Decline in the ALSFRS-R score was not accelerated during the 6-month follow-up period. Two repeated intrathecal injections of autologous MSCs were safe and feasible throughout the duration of the 12-month follow-up period. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:590-597

Cell polarization and directional cell migration can display random, persistent, and oscillatory dynamic patterns. However, it is not clear whether these polarity patterns can be explained by the same underlying regulatory mechanism. Here, we show that random, persistent, and oscillatory migration accompanied by polarization can simultaneously occur in populations of melanoma cells derived from tumors with different degrees of aggressiveness. We demonstrate that all of these patterns and the probabilities of their occurrence are quantitatively accounted for by a simple mechanism involving a spatially distributed, mechanochemical feedback coupling the dynamically changing extracellular matrix (ECM)-cell contacts to the activation of signaling downstream of the Rho-family small GTPases. This mechanism is supported by a predictive mathematical model and extensive experimental validation, and can explain previously reported results for diverse cell types. In melanoma, this mechanism also accounts for the effects of genetic and environmental perturbations, including mutations linked to invasive cell spread. The resulting mechanistic understanding of cell polarity quantitatively captures the relationship between population variability and phenotypic plasticity, with the potential to account for a wide variety of cell migration states in diverse pathological and physiological conditions. cell polarization | cell migration | mechanochemical feedback | Rho-family small GTPases | extracellular matrix C ell migration involves complex interactions with the extracellular matrix (ECM) (1-4). Beyond providing cells with the substratum for adhesion and traction during the migration process, the ECM can activate signaling networks through biochemical engagement of the integrin complexes within focal adhesions (FAs) (5-7). The signaling pathways activated by integrins can impinge on the Rho-family small GTPases that are thought to be central regulators of cell polarity and migration (8-10). Varying ECM density can differentially control activation of two proteins belonging to this family, Rac1 and RhoA, which frequently display antagonistic interactions (11,12). Activation of Rac1 and RhoA can in turn regulate the mechanical properties of the cell, thus influencing how the cell interfaces with complex local organization of ECM fibers (13-15). The intricate nature of this ECM-Rac1-RhoA feedback interaction and the wide diversity of topographic ECM structures have made comprehensive analysis of the resulting cell migration behavior very challenging.In vivo cell migration can display diverse dynamic patterns. It can vary from random exploratory migration characterized by poor FA formation, frequent pseudopod extension, and a lack of stress fibers in dense 3D ECM (so-called 3D cell migration) to highly persistent migration along single ECM fibers in sparse 3D ECM (essentially 1D cell migration) (16-18). Recently, oscillatory migration patterns have also been observed following perturbation of cytoskeletal components, with cells retra...