DNA topoisomerase II beta as a molecular switch in neural differentiation of mesenchymal stem cells


Isik S., Zaim M., Yildiz M. T. , Negis Y., Kunduraci T., Karakas N., ...More

ANNALS OF HEMATOLOGY, vol.94, no.2, pp.307-318, 2015 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 94 Issue: 2
  • Publication Date: 2015
  • Doi Number: 10.1007/s00277-014-2209-7
  • Title of Journal : ANNALS OF HEMATOLOGY
  • Page Numbers: pp.307-318

Abstract

Two isoforms of DNA topoisomerase II (topo II) have been identified in mammalian cells, named topo II alpha and topo II beta. Topo II alpha plays an essential role in segregation of daughter chromosomes and thus for cell proliferation in mammalian cells. Unlike its isozyme topo II alpha, topo II beta is greatly expressed upon terminal differentiation of neuronal cells. Although there have been accumulating evidence about the crucial role of topo II beta in neural development through activation or repression of developmentally regulated genes at late stages of neuronal differentiation, there have been no reports that analyzed the roles of topo II beta in the neural trans differentiation process of multipotent stem cells. Terminal differentiation of neurons and transdifferentiation of Mesenchymal Stem Cells (MSCs) are two distinct processes. Therefore, the functional significance of topo II beta may also be different in these differentiation systems. MSC transdifferentiation into neuron-like cells represents an useful model to further validate the role of topo II beta in neuronal differentiation. The aim of this study is to evaluate the subset of genes that are regulated in neural transdifferentiation of bone marrow-derived human MSCs (BM-hMSCs) in vitro and find genes related with topo II beta. For this purpose, topo II beta was silenced by specific small interfering RNAs in hMSCs and cells were induced to differentiate into neuron-like cells. Differentiation and silencing of topo II beta were monitored by real-time cell analysis and also expressions of topo II isoforms were analyzed. Change in transcription patterns of genes upon topo II beta silencing was identified by DNA microarray analysis, and apparently genes involved in regulation of several ion channels and transporters, vesicle function, and cell calcium metabolism were particularly affected by topo II beta silencing suggesting that topoII beta silencing can significantly alter the gene expression pattern of genes involved in variety of biological processes and signal transduction pathways including transcription, translation, cell trafficking, vesicle function, transport, cell morphology, neuron guidance, growth, polarity, and axonal growth. It appears that the deregulation of these pathways may contribute to clarify the further role of topo II beta in neural differentiation.