Pan-neuronal maturation but not neuronal subtype differentiation of adult neural stem cells is mechanosensitive

Most past studies of the biophysical regulation of stem cell differentiation have focused on initial lineage commitment or proximal differentiation events. It would be valuable to understand whether biophysical inputs also influence distal endpoints more closely associated with physiological function, such as subtype specification in neuronal differentiation. To explore this question, we cultured adult neural stem cells (NSCs) on variable stiffness ECMs under conditions that promote neuronal fate commitment for extended time periods to allow neuronal subtype differentiation. We find that ECM stiffness does not modulate the expression of NeuroD1 and TrkA/B/C or the percentages of pan-neuronal, GABAergic, or glutamatergic neuronal subtypes. Interestingly, however, an ECM stiffness of 700 Pa maximizes expression of pan-neuronal markers. These results suggest that a wide range of stiffnesses fully permit pan-neuronal NSC differentiation, that an intermediate stiffness optimizes expression of pan-neuronal genes, and that stiffness does not impact commitment to particular neuronal subtypes

Guiding the osteogenic fate of mouse and human mesenchymal stem cells through feedback system control

Stem cell-based disease modeling presents unique opportunities for mechanistic elucidation and therapeutic targeting. The stable induction of fate-specific differentiation is an essential prerequisite for stem cell-based strategy. Bone morphogenetic protein 2 (BMP-2) initiates receptor-regulated Smad phosphorylation, leading to the osteogenic differentiation of mesenchymal stromal/stem cells (MSC) in vitro; however, it requires supra-physiological concentrations, presenting a bottleneck problem for large-scale drug screening. Here, we report the use of a double-objective feedback system control (FSC) with a differential evolution (DE) algorithm to identify osteogenic cocktails of extrinsic factors. Cocktails containing significantly reduced doses of BMP-2 in combination with physiologically relevant doses of dexamethasone, ascorbic acid, beta-glycerophosphate, heparin, retinoic acid and vitamin D achieved accelerated in vitro mineralization of mouse and human MSC. These results provide insight into constructive approaches of FSC to determine the applicable functional and physiological environment for MSC in disease modeling, drug screening and tissue engineering

The Extracellular Matrix, Growth Factors and Morphogens in Biomaterial Design and Tissue Engineering

Cells, morphogens, growth factors, and custom scaffolds are the critical ingredients for successful tissue regeneration in which morphogens and growth factors function sequentially. Extensive studies, in vitro and in vivo, have been made to explore the mechanisms and the roles played by these molecules. As a consequence, precise, localized control over the signaling of these factors and appropriate strategy selection, depending on the tissue or organ to be repaired or regenerated, is known to permit specific management of regenerative processes. The first part of the chapter examines natural ECMs which are a set of molecules secreted by cells that provide structural and biochemical support to the surrounding cells. ECMs also perform many other functions, such as actively regulating cell function through the control of biochemical gradients, cell density, spatial organization, and ligand attachment, thus influencing various types of cell processes. Subsequently, growth factors and morphogens are examined in greater depth to clarify to what degree progress has been made into improving methodologies and functionality and, perhaps, to hint at what remains to be done for the future of tissue engineering

Role for Mechanotransduction in Macrophage and Dendritic Cell Immunobiology

Item does not contain fulltextTissue homeostasis is not only controlled by biochemical signals but also through mechanical forces that act on cells. Yet, while it has long been known that biochemical signals have profound effects on cell biology, the importance of mechanical forces has only been recognized much more recently. The types of mechanical stress that cells experience include stretch, compression, and shear stress, which are mainly induced by the extracellular matrix, cell-cell contacts, and fluid flow. Importantly, macroscale tissue deformation through stretch or compression also affects cellular function.Immune cells such as macrophages and dendritic cells are present in almost all peripheral tissues, and monocytes populate the vasculature throughout the body. These cells are unique in the sense that they are subject to a large variety of different mechanical environments, and it is therefore not surprising that key immune effector functions are altered by mechanical stimuli. In this chapter, we describe the different types of mechanical signals that cells encounter within the body and review the current knowledge on the role of mechanical signals in regulating macrophage, monocyte, and dendritic cell function