Dopaminergic‐like cells from epigenetically reprogrammed mesenchymal stem cells

Zhiying Zhang,Arshak R Alexanian

doi:10.1111/j.1582-4934.2012.01591.x

Zhiying Zhang, Arshak R Alexanian

Open Access

https://doi.org/10.1111/j.1582-4934.2012.01591.x

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Abstract

A number of recent studies have examined the ability of stem cells derived from different sources to differentiate into dopamine-producing cells and ameliorate behavioural deficits in Parkinsonian models. Recently, using the approach of cell reprogramming by small cell-permeable biological active compounds that involved in the regulation of chromatin structure and function, and interfere with specific cell signalling pathways that promote neural differentiation we have been able to generate neural-like cells from human bone marrow (BM)-derived MSCs (hMSCs). Neurally induced hMSCs (NI-hMSCs) exhibited several neural properties and exerted beneficial therapeutic effect on tissue preservation and locomotor recovery in spinal cord injured rats. In this study, we aimed to determine whether hMSCs neuralized by this approach can generate dopaminergic (DA) neurons. Immunocytochemisty studies showed that approximately 50–60% of NI-hMSCs expressed early and late dopaminergic marker such as Nurr-1 and TH that was confirmed by Western blot. ELISA studies showed that NI-hMSCs also secreted neurotrophins and dopamine. Hypoxia preconditioning prior to neural induction increased hMSCs proliferation, viability, expression TH and the secretion level of dopamine induced by ATP. Taken together, these studies demonstrated that hMSCs neurally modified by this original approach can be differentiated towards DA-like neurons.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive degeneration of nigrostriatal DA neurons.At present, replacement of the progressively degenerated DA neurons through cells transplantation is considered to have the most potential as a therapy [1,2]
To investigate DA differentiation ability of cells first we performed immunocytochemistry to study the expression of DA specific markers Nurr1 and tyrosine hydroxylase (TH) in human bone marrow (BM)-derived MSCs (hMSCs) and NI-hMSCs grown in normoxic (21%O2, 5% CO2) or hypoxic (4%O2, 5% CO2, 91%N2) conditions
Results showed that the small percentage of hMSCs were immunopositive to Nurr1 (1.25 ± 0.53%) and TH (0.97 ± 0.42)% (Fig. 1A–G)

Summary

Introduction

Replacement of the progressively degenerated DA neurons through cells transplantation is considered to have the most potential as a therapy [1,2]. Cells generated by this technology can Recently, several new reprogramming strategies have been attempted to overcome several safety and efficiency issues associated with genetic approach. The chemical (chemical genetics) approach is one of them which could be a safer, easier and more feasible alternative This new strategy of reprogramming is still in its infancy and mostly has been used to increase the efficiency of some of the iPS reprogramming technologies [9], recently several studies showed the effectiveness of this approach for transdifferentiation (lineage switches) of cells [10,11,12]

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