Mechanically induced osteogenic lineage commitment of stem cells

Abstract

Bones adapt to accommodate the physical forces they experience through changes in architecture and mass. Stem cells differentiate into bone-forming osteoblasts, and mechanical stimulation is involved in this process. Various studies have applied controlled mechanical stimulation to stem cells and investigated the effects on osteogenic lineage commitment. These studies demonstrate that physical stimuli can induce osteogenic lineage commitment. Tension, fluid shear stress, substrate material properties, and cell shape are all factors that influence osteogenic differentiation. In particular, the level of tension is important. Also, rigid substrates with stiffness similar to collagenous bone induce osteogenic differentiation, while softer substrates induce other lineages. Finally, cells allowed to adhere over a larger area are able to differentiate towards the osteogenic lineage while cells adhering to a smaller area are restricted to the adipogenic lineage. Stem cells are able to sense their mechanical environments through various mechanosensors, including the cytoskeleton, focal adhesions, and primary cilia. The cytoskeleton provides a structural frame for the cell, and myosin interacts with actin to generate cytoskeletal tension, which is important for mechanically induced osteogenesis of stem cells. Adapter proteins link the cytoskeleton to integrins, which attach the cell to the substrate, forming a focal adhesion. A variety of signaling proteins are also associated with focal adhesions. Forces are transmitted to the substrate at these sites, and an intact focal adhesion is important for mechanically induced osteogenesis. The primary cilium is a single, immotile, antenna-like structure that extends from the cell into the extracellular space. It has emerged as an important signaling center, acting as a microdomain to facilitate biochemical signaling. Mechanotransduction is the process by which physical stimuli are converted into biochemical responses. When potential mechanosensors are disrupted, the activities of components of mechanotransduction pathways are also inhibited, preventing mechanically induced osteogenesis. Calcium, mitogen-activated protein kinase/extracellular signal-regulated kinase, Wnt, Yes-associated protein/transcriptional coactivator with PDZ-binding motif and RhoA/Rho kinase signaling are some of the mechanotransduction pathways proposed to be important. In this review, types of mechanical stimuli, mechanosensors, and key pathways involved in mechanically induced osteogenesis of stem cells are discussed.

Modulation of microenvironment for controlling the fate of periodontal ligament cells: the role of Rho/ROCK signaling and cytoskeletal dynamics

“…Mechanical stress-induced alterations in cell shape and structure are vital for the control of cell growth, migration, differentiation, and apoptosis (Chicurel et al 1998). Mechanical forces and matrix mechanical properties impact the cytoskeletal tension and regulate stem cell lineage commitment in part by Rho/ROCK signaling (Chen and Jacobs 2013;Ivanovska et al 2015). Recent studies shed light on the striking roles of transcriptional regulators Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), which are the downstream effectors of the Hippo pathway (Pan 2010), in mechanotransduction.…”

Barium titanate nanoparticles and hypergravity stimulation improve differentiation of mesenchymal stem cells into osteoblasts

“…1 This process is called mechanotransduction, and the responsible structures sensitive to mechanical forces are most probably cytoskeleton elements. 2 A number of studies have demonstrated that cells are sensitive to several kinds of physical cues (shear stress, topography, mechanical deformation, etc), influencing cell migration, 3 differentiation, 4 and proliferation. 5 Among these stimuli, gravity is required for the correct development of land-based organisms, and in particular for the skeleton and for the muscle and nervous systems.…”

<b>Tensile stress stimulates the expression of osteogenic cytokines/growth factors and matricellular proteins in the mouse cranial suture at the site of osteoblast differ</b><b>entiation </b>

“…Moreover, some ECMs are known to modulate cell functions and have been termed as 'matricellular' proteins (3). During the process of osteogenesis in vivo, MSCs proliferate and then differentiate into osteoblastic cell lineage in a microenvironment associated with a heterogeneous population of cells and ECMs, under the influence of cell-cell and cell-matrix interactions (8). Therefore, for better understanding of the mechanism of mechanical stress-stimulated osteoblastogenesis, a global analysis needs to be performed to examine the cellular response to mechanical stress in a microenvironment similar to that found in vivo.…”

“…Mechanical stress controls bone mass by affecting recruitment of osteoprogenitors as well as osteoblast differentiation from mesenchymal stem cells (MSCs) in the bone tissue (7,8). Elucidation of the precise mechanisms involved in the osteoblastogenesis stimulated by mechanical stress, especially the mechanism for osteogenic differentiation of MSCs, will contribute to the progress of regenerative medicine for effective production of bone tissue from MSC sources.…”

“…Thus, for the first time we demonstrated the mechanical stimulation of Cyr61/CCN1 expression in osteogenic cells in an ex vivo system. These results suggest the importance of matricellular proteins along with the cytokine-mediated signaling for the mechanical regulation of MSC proliferation and differentiation into osteoblastic cell lineage in vivo.Mechanical stress controls bone mass by affecting recruitment of osteoprogenitors as well as osteoblast differentiation from mesenchymal stem cells (MSCs) in the bone tissue (7,8). Elucidation of the precise mechanisms involved in the osteoblastogenesis stimulated by mechanical stress, especially the mechanism for osteogenic differentiation of MSCs, will contribute to the progress of regenerative medicine for effective production of bone tissue from MSC sources.…”