Abstract
The current study investigated the combinatorial effect of cyclic strain and electrical stimulation on neural differentiation potential of rat bone marrow-derived mesenchymal stem cells (BMSCs) under epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) inductions in vitro. We developed a prototype device which can provide cyclic strain and electrical signal synchronously. Using this system, we demonstrated that cyclic strain and electrical co-stimulation promote the differentiation of BMCSs into neural cells with more branches and longer neurites than strain or electrical stimulation alone. Strain and electrical co-stimulation can also induce a higher expression of neural markers in terms of transcription and protein level. Neurotrophic factors and the intracellular cyclic AMP (cAMP) are also upregulated with co-stimulation. Importantly, the co-stimulation further enhances the calcium influx of neural differentiated BMSCs when responding to acetylcholine and potassium chloride (KCl). Finally, the phosphorylation of extracellular-signal-regulated kinase (ERK) 1 and 2 and protein kinase B (AKT) was elevated under co-stimulation treatment. The present work suggests a synergistic effect of the combination of cyclic strain and electrical stimulation on BMSC neuronal differentiation and provides an alternative approach to physically manipulate stem cell differentiation into mature and functional neural cells in vitro.
Highlights
Traumatic nervous system injuries, stroke, and many neurological disorders are characterized by the loss of neuronal functions
We examined the effect of the association of mechanical strain with electrical stimulation on bone marrow-derived mesenchymal stem cells (BMSC) neural differentiation, which was not observed under each individual stimulation
The rat BMSCs were preinduced for 7 days, and pyramidalshaped cell bodies and extended short neurites, reminiscent of dendrites, could be identified
Summary
Stroke, and many neurological disorders are characterized by the loss of neuronal functions. The damaged neural tissue rarely recovers spontaneously due to extremely low endogenous regenerative capacity and poor migrating ability of the neural stem cells. Stem-cell-mediated therapy has shown a great preclinical potential for neural injury and Abbreviations: BMSC, bone marrow-derived mesenchymal stem cells; EF, electrical field; EGF, epidermal growth factor; FGF2, fibroblast growth factor 2; cAMP, cyclic AMP; KCl, potassium chloride; ERK, extracellular-signal-regulated kinase; AKT, protein kinase B; DMEM-LG, Dulbecco’s modified Eagle medium-low glucose; NSE, neuron-specific enolase; MAP2, microtubule-associated protein 2; NT-3, neurotrophin 3; NT-4, neurotrophin 4; BDNF, brain-derived neurotrophic factorl; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Mesenchymal stem cells (MSCs) have been widely used as a cell therapy to treat various diseases including bone diseases, cardiovascular diseases, autoimmune diseases, and inflammatory diseases (Shafei et al, 2017; Molendijk et al, 2018; Su et al, 2018; Yan et al, 2018). Animal experiments showed that MSC-differentiated neuronal cells are beneficial for neuronal regeneration (Brazelton et al, 2000; Takizawa, 2003; Mimura et al, 2005; Bahat-Stroomza et al, 2009; Hayase et al, 2009)
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