Abstract
JC virus (JCV), a common human polyomavirus, is the etiological agent of the demyelinating disease, progressive multifocal leukoencephalopathy (PML). In addition to its role in PML, studies have demonstrated the transforming ability of the JCV early protein, T-antigen, and its association with some human cancers. JCV infection occurs in childhood and latent virus is thought to be maintained within the bone marrow, which harbors cells of hematopoietic and non-hematopoietic lineages. Here we show that non-hematopoietic mesenchymal stem cells (MSCs) isolated from the bone marrow of JCV T-antigen transgenic mice give rise to JCV T-antigen positive cells when cultured under neural conditions. JCV T-antigen positive cells exhibited neural crest characteristics and demonstrated p75, SOX-10 and nestin positivity. When cultured in conditions typical for mesenchymal cells, a population of T-antigen negative cells, which did not express neural crest markers arose from the MSCs. JCV T-antigen positive cells could be cultured long-term while maintaining their neural crest characteristics. When these cells were induced to differentiate into neural crest derivatives, JCV T-antigen was downregulated in cells differentiating into bone and maintained in glial cells expressing GFAP and S100. We conclude that JCV T-antigen can be stably expressed within a fraction of bone marrow cells differentiating along the neural crest/glial lineage when cultured in vitro. These findings identify a cell population within the bone marrow permissible for JCV early gene expression suggesting the possibility that these cells could support persistent viral infection and thus provide clues toward understanding the role of the bone marrow in JCV latency and reactivation. Further, our data provides an excellent experimental model system for studying the cell-type specificity of JCV T-antigen expression, the role of bone marrow-derived stem cells in the pathogenesis of JCV-related diseases and the opportunities for the use of this model in development of therapeutic strategies.
Highlights
JC virus (JCV) is a ubiquitous human polyomavirus and the etiological agent of the demyelinating disease, progressive multifocal leukoencephalopathy (PML) [1]
Given the rarity of cells of neuroepithelial origin in bone marrow aspirates and the possibility of their in vitro enrichment in cultures of mesenchymal stem cells (MSCs), we first isolated the MSC fraction of the bone marrow from JCV T-antigen transgenic mice by the virtue of their adherence to tissue culture plastic in aMEM media supplemented with 20% fetal bovine serum which supports the growth of mesenchymal cells
MSCs isolated from the bone marrow of JCV T-antigen transgenic mice were subcultured and maintained in serum-free neural stem cell media supplemented with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) or in aMEM supplemented with 20% fetal bovine serum
Summary
JC virus (JCV) is a ubiquitous human polyomavirus and the etiological agent of the demyelinating disease, progressive multifocal leukoencephalopathy (PML) [1]. PML was a rare disease, recent reports have shown an increased occurrence of PML related to the treatment of patients with monoclonal antibody therapies such as natalizumab, rituximab and efalizumab [3]. It has been hypothesized that JCV persistently infects bone marrow hematopoietic stem/progenitor cells and that circulating B-cells, which arise from the hematopoietic lineage, most likely transport the virus to the sites of latency or lytic replication within the brain [3]. Recent studies of PML occurring in multiple sclerosis patients have shown that CD34 positive hematopoietic cells mobilized to the circulation by natalizumab do not contain JCV DNA [7]. While JCV DNA can be extracted from bone marrow aspirates, the cells of origin in which this virus persists within the bone marrow and the exact role of hematopoietic cells in the pathogenesis of JCV related diseases remain unclear
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