Genetic modification of H2AX renders mesenchymal stromal cell-derived dopamine neurons more resistant to DNA damage and subsequent apoptosis

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• 作者：Peizhou Jiang¹ ; ^{jiang.peizhou@mayo.edu" class="auth_mail" title="E-mail the corresponding author} ; Peng Huang² ; Shu-Hui Yen¹ ; Abba C. Zubair² ; Dennis W. Dickson¹ ; ^{dickson.dennis@mayo.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：DNA damage ; H2AX ; lentivirus infection ; mesenchymal stromal cells ; Parkinson's disease
• 刊名：Cytotherapy
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：18
• 期：12
• 页码：1483-1492
• 全文大小：1755 K

文摘

Aberrant production of reactive oxygen species (ROS) and its impact on the integrity of genomic DNA have been considered one of the major risk factors for the loss of dopaminergic neurons in Parkinson's disease (PD). Stem cell transplantation as a strategy to replenish new functional neurons has great potential for PD treatment. However, limited survival of stem cells post-transplantation has always been an obstacle ascribed to the existence of neurotoxic environment in PD patients.

Methods

To improve the survival of transplanted stem cells for PD treatment, we explored a new strategy based on the function of the H2AX gene (H2A histone family, member X) in determination of DNA repair and cell apoptosis. We introduced a mutant form Y142F of H2AX into dopamine (DA) neuron-like cells differentiated from bone marrow–derived mesenchymal stromal cells (BMSCs).

Results

Expression of H2AX(Y142F) renders DA neuron-like cells more resistant to DNA damage and subsequent cell death induced by ultraviolet irradiation and 1-methyl-4-phenylpyridinium (MPP+) treatment.

Discussion

This is a meaningful attempt to improve the sustainability of BMSC-derived dopamine neurons under a brain neurotoxic environment. Further studies are needed to evaluate the implications of our findings in stem cell therapy for PD and related diseases.