Abstract
Human bone marrow contains two major cell types, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). MSCs possess self-renewal capacity and pluripotency defined by their ability to differentiate into osteoblasts, chondrocytes, adipocytes and muscle cells. MSCs are also known to differentiate into neurons and glial cells in vitro, and in vivo following transplantation into the brain of animal models of neurological disorders including ischemia and intracerebral hemorrhage (ICH) stroke. In order to obtain sufficient number and homogeneous population of human MSCs, we have clonally isolated permanent and stable human MSC lines by transfecting primary cell cultures of fetal human bone marrow MSCs with a retroviral vector encoding v-myc gene. One of the cell lines, HM3.B10 (B10), was found to differentiate into neural cell types including neural stem cells, neurons, astrocytes and oligodendrocytes in vitro as shown by expression of genetic markers for neural stem cells (nestin and Musashi1), neurons (neurofilament protein, synapsin and MAP2), astrocytes (glial fibrillary acidic protein, GFAP) and oligodendrocytes (myelin basic protein, MBP) as determined by RT-PCR assay. In addition, B10 cells were found to differentiate into neural cell types as shown by immunocytochical demonstration of nestin (for neural stem cells), neurofilament protein and β-tubulin III (neurons) GFAP (astrocytes), and galactocerebroside (oligodendrocytes). Following brain transplantation in mouse ICH stroke model, B10 human MSCs integrate into host brain, survive, differentiate into neurons and astrocytes and induce behavioral improvement in the ICH animals. B10 human MSC cell line is not only a useful tool for the studies of organogenesis and specifically for the neurogenesis, but also provides a valuable source of cells for cell therapy studies in animal models of stroke and other neurological disorders.
Highlights
Human bone marrow contains two major cell types, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs)
In addition to growth factors, the RT-PCR study has demonstrated that both primary human MSCs and B10 cells express mRNA for VEGFR, CXCR4 and c-kit, cellular receptors known for close involvement in cellular migration (Figure 10). These results indicate that the pathways involving stem cell factor (SCF)/c-kit, stromal cell derived factor-1 (SDF-1)/CXCR4 and vascular endothelial cell growth factor (VEGF)/VEGFR are important in the migration of MSCs to the sites of intracerebral hemorrhage (ICH) brain damage and to corpus callosum and hippocampus
We report the generation of permanent, stable human mesenchymal stem cell (MSC) lines with properties of selfrenewal and pluripotency
Summary
Human bone marrow contains two major cell types, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). MSCs possess self-renewal capacity and pluripotency defined by their ability to differentiate into bone, fat, cartilage and muscle [1,2,3,4]. Two major types of stroke are ischemic stroke and intracerebral hemorrhage (ICH), and ICH represents at least 15% of all strokes in the western population [8], while in Asia including China, Japan and Korea ICH occupies considerably higher proportion at 50–60%[9]. ICH is a lethal stroke type, as mortality approaches 50% and neurological disability in survivors is common. Since medical therapy against ICH such as mechanical removal of hematoma, prevention of edema formation by drugs, and reduction of intracranial pressure, shows only limited effectiveness, alternative approach is required [10,11]
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