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

Jerran Santos,Thibaut Hubert,Bruce K Milthorpe

doi:10.3390/cells9030619

Jerran Santos, Thibaut Hubert + Show 1 more

Open Access

https://doi.org/10.3390/cells9030619

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Journal: Cells	Publication Date: Mar 4, 2020
Citations: 24	License type: CC BY 4.0

Affiliation: University of Technology Sydney, Université de Lorraine

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.

Highlights

Regenerative and translational medicine is a rapidly expanding area made possible by the availability of an abundant source of stem cells, autologous adult mesenchymal stem cells acquired from lipoaspirates termed adipose derived stem cells (ADSCs)
In this study we presented the temporal treatment of Valproic acid (VPA) on ADSCs and the proteomic, Bioplex, interaction network and pathway analysis
Inhibiting histone deacetylase (HDAC), it promotes the expression of suppressor of cytokine signaling 5 (SOCS5), which downregulates the JAK/STAT pathway

Summary

Introduction

Regenerative and translational medicine is a rapidly expanding area made possible by the availability of an abundant source of stem cells, autologous adult mesenchymal stem cells acquired from lipoaspirates termed adipose derived stem cells (ADSCs). The application of autologous ADSCs to neural regeneration and repair therapies is of great interest due to the potential to reverse or limit the exacerbation of injuries that have severe effects on the quality of life while avoiding rejection [1]. At optimized concentrations and short treatment times, chemicals such as beta-mercaptoethanol (BME) and dimethylsulfoxide (DMSO), have shown the potential to induce a structural and molecular phenotype in stem cells that resemble differentiating neural cells [2,3]. Not surprisingly, these molecules had negative effects inducing a range of stress and apoptotic markers with an increasing treatment time frame. Less harsh chemicals with similar actions, such as butylated hydroxyanisole (BHA), retinoic acid (RA) and other chemical

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