Introduction Human bone marrow stromal cells hBMSCs also

Introduction Human bone marrow stromal purchase GKPIPNPLLGLDST (hBMSCs, also known as bone marrow-derived mesenchymal stem cells) contain a population of progenitor cells, and a subpopulation of skeletal stem cells (hSSCs) known to be able to recreate cartilage, bone, stroma that supports hematopoiesis and marrow adipocytes. Recently, hSSCs have been found to reside as pericytes on bone marrow sinusoids, and to participate in vascular stability (Sacchetti et al., 2007). As such, human bone marrow stromal stem/progenitor cells (hSSCs/BMSCs, collectively referred to as hBMSCs below) continue to be a cornerstone in the fields of basic science and medicine due to their regenerative, reparative, and angiogenic properties. These cells are attractive candidates for cell-based tissue regeneration because of their ability to be extensively propagated in culture while retaining their differentiation potential, although overexpansion can lead to senescence and inability to differentiate. Transcription factors [such as RUNX2 and β-CATENIN (CTNNB1) (Ceccarelli et al., 2013; Liu et al., 2009; Takada, et al., 2009)] and signaling molecules [such as WNTs, TGF-β and VEGF (Yang et al., 2012)] work in concert to regulate BMSC differentiation. Studies in developmental biology have revealed that transcription factors are key regulators of embryonic morphogenesis, and play a leading role in the control and regulation of the differentiation pathways of stromal cells. For BMSCs in particular, the main transcription factors that drive differentiation during development are Cbfa-1/Runx2 and Osterix (Sp7) for bone formation (Komori, 2010; Schroeder et al., 2005), while Sox9 and modulation of Wnt/β-catenin signaling pathways drive chondrogenesis (Chen CH et al., 2013; Day et al., 2005; Mayer-Wagner et al., 2011). BMSC differentiation is heavily influenced by molecular and biophysical-regulating factors present within their environment. In culture, these factors include nutrient media, scaffold constructs, and biochemical cues as well as biophysical information exchange. The BMSCs\' first line of interaction is with their extracellular matrix (ECM), which serves as an endogenous scaffold. Once proliferation is established in the ECM, differentiation and continued proliferation onto extracellular structures, such as natural or synthetic scaffolds, begin. Sundelacruz et al. reported that manipulation of the membrane potential of cultured BMSCs can influence their fate and differentiation, along the adipogenic and osteogenic lineages (Sundelacruz et al., 2008, 2009). These findings suggest that it may be possible to achieve an unprecedented level of control over BMSC differentiation using exogenous factors such as an electromagnetic field (EMF). In agreement with this assertion are recent studies showing that extremely low frequency (0–100Hz) electromagnetic fields (ELF-EMF) affect numerous biological functions such as cell differentiation (Funk et al., 2009), gene expression (Mousavi et al., 2014), and cell fate (Kim et al., 2013), and have been reported to promote the release of necessary growth factors and enhance the differentiation process (Funk and Monsees, 2006). During human development, lineage-committed cells of the three embryonic germ layers migrate and proliferate in appropriate directions to form tissues and organs. Throughout this biological development process, electric fields (EFs) arise in the form of endogenous ionic currents (Levin, 2003; McGaig et al., 2005). While endogenous EFs are present in all developing and regenerating animal tissues, their existence and potential impact on tissue regeneration and repair have been largely ignored. In order to guide cells during migration, endogenous field gradients develop in the embryo by forming voltage gradients between the intracellular and extracellular environment (Levin, 2012a). These voltage gradients are generated by passive sodium (Na+) uptake from the extracellular environment creating potential differences that are time and location specific, and are switched on and off at different developmental stages (Levin, 2003; Levin and Stevenson, 2012b). In most cells, sodium (Na+) and chloride (Cl−) dominate the outside of the plasma membrane and potassium (K+) and organic molecules such as anions (A−) dominate the inside (Sherwood et al., 2005). Na+ and Cl− are the major solutes in the extracellular fluid. These ionic currents are responsible for changes in voltage gradients that correlate with morphogenetic events during growth and patterning (size, shape, and position) of the organism (Hotary and Robinson, 1990; Hotary and Robinson, 1992; Metcalf et al., 1994). The unequal distribution of a few key ions between the intra- and extra-cellular fluid, and their selective movement through the plasma membrane, governs the electrical properties of the membrane. All plasma membranes have a membrane potential, which electrically polarizes them; therefore, the membrane potential (Vmem) refers to a separation of charges across the membrane (Sherwood et al., 2005). Fluctuations in potential serve as electrical signals. These electrical charges are carried by ions. All living cells have a membrane potential, with the cell\'s interior being slightly more negative than the fluid surrounding the cell when the cell is electrically at rest. Charges are separated across the plasma membrane, and any time the value of the Vmem is anything other than 0mV, in either the positive or negative direction, the membrane is in a state of polarization. The magnitude of the polarization potential is directly proportional to the number of positive and negative charges separated by the membrane. Changes in Vmem are brought about by changes in ion movement across the membrane. Triggering events such as exposure to EMF can cause changes in membrane permeability. Gated-channels have movable folds in the proteins that can alternately be open, permitting ion passage through the channel, or closed, preventing ion passage through the channel (Fig. 1). Like many proteins, these channels can be inherently flexible molecules whose conformations can be altered in response to external factors (Sherwood et al., 2005). Voltage-gated ion channels, in particular, open or close in response to changes in membrane potential.