Valproic Acid Promotes Early Neural Differentiation in Adult Mesenchymal Stem Cells Through Protein Signalling Pathways

Abstract

Regenerative medicine is a rapidly expanding area in research and clinical applications. Therapies involving the use of small molecule chemicals aim to simplify the creation of specific drugs for clinical applications. Adult mesenchymal stem cells have recently shown the capacity to differentiate into several cell types applicable for regenerative medicine (specifically neural cells, using chemicals). Valproic acid was an ideal candidate due to its clinical stability. It has been implicated in the induction of neural differentiation; however, the mechanism and the downstream events were not known. In this study, we showed that using valproic acid on adult mesenchymal stem cells induced neural differentiation within 24 h by upregulating the expression of suppressor of cytokine signaling 5 (SOCS5) and Fibroblast growth factor 21 (FGF21), without increasing the potential death rate of the cells. Through this, the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway is downregulated, and the mitogen-activated protein kinase (MAPK) cascade is activated. The bioinformatics analyses revealed the expression of several neuro-specific proteins as well as a range of functional and structural proteins involved in the formation and development of the neural cells.

Molecular Mechanisms Involved in Neural Substructure Development during Phosphodiesterase Inhibitor Treatment of Mesenchymal Stem Cells

“…The cells were harvested for proteomic analysis as per Santos et al [ 27 ] for liquid chromatography-tandem mass spectrometry (LC-MS/MS), at time points of 0, 3, 6 and 24 h post treatment, were completed in biological and technical triplicates. Culture media was collected from each well in 2 mL Eppendorf tubes and stored at −80 °C for later Bioplex and toxicity assays.…”

“…Bioplex analysis was performed as per Santos et al [ 27 ] with 500 μL aliquots collected at timepoints and controls as follows: DMEM control, starve, B27 control, 0, 3, 6 and 24 h. The assay was performed using Bioplex human 27-plex (M50-0KCAF0Y Bio-Rad Laboratories, Hercules, CA, USA). The data analysis was completed using DanteR software (DanteR version 1.0.0.10, R version 2.12.0, The R Foundation for Statistical Computing, Auckland, New Zealand) [ 77 ].…”

“…Several chemicals have been cited in the literature and included as parts of chemical cocktails that reportedly cause neural induction, which may include small-molecule chemicals, growth factors, hormones or other proteins, [ 23 , 24 , 25 , 26 , 27 ] such as those containing indomethacin, insulin and isobutylmethylxanthine (IBMX) [ 28 ]; and those containing brain-derived neurotrophic factor (BDNF) and retinoic acid [ 29 ]. The previous use of small-molecule chemicals such as β-mercaptoethanol (BME), butylated hydroxyanisole (BHA), valproic acid (VA) and dimethyl-sulfoxide (DMSO) produced differentiated cells within a far shorter time than conventional methods, sometimes within minutes or hours [ 23 ].…”

Adipose-Derived Stromal/Stem Cells

“…This Special Issue covers research articles investigating various adipose tissues as a source for ASC isolation [ 1 , 2 , 3 ], specific cultures methods to enhance proliferation or viability [ 4 , 5 , 6 , 7 ], and the differentiation capacity [ 8 , 9 , 10 , 11 , 12 ]. Furthermore, other studies highlight aspects of various diseases [ 13 , 14 ], the immunosuppressive potential of ASCs and their derivates [ 15 ] or the in vivo tracking of transplanted ASCs [ 16 ].…”

“…Others studied various effects of differentiation events induced by differentiation-inducing agents. Using valproic acid, the induced neural differentiation of ASCs was demonstrated by the upregulation of characteristic neuro-specific factors [ 8 ]. Zöller and co-workers showed that collagen I was able to modulate lipogenesis and adiponectin expression, and hypothesized that this could contribute to age-related metabolic disorders [ 10 ].…”