S. Ausim Azizi

A population of human brain parenchymal cells express markers of glial, neuronal and early neural cells and differentiate into cells of neuronal and glial lineages.

Glial fibrillary acidic protein (GFAP)‐positive cells derived from the neurogenic areas of the brain can be stem/progenitor cells and give rise to new neurons in vitro and in vivo. We report here that a population of GFAP‐positive cells derived from fetal human brain parenchyma coexpress markers of early neural and neuronal cells, and have neural progenitor cell characteristics. We used a monolayer culture system to expend and differentiate these cells. During the initial proliferative phase, all cells expressed GFAP, nestin and low levels of βIII‐tubulin. When these cells were cultured in serum and then basic fibroblast growth factor, they generated two distinct progenies: (i) βIII‐tubulin‐ and nestin‐positive cells and (ii) GFAP‐ and nestin‐positive cells. These cells, when subsequently cultured in serum‐free media without growth factors, ceased to proliferate and differentiated into two major neural cell classes, neurons and glia. In the cells of neuronal lineage, nestin expression was down‐regulated and βIII‐tubulin expression became robust. Cells of glial lineage differentiated by down‐regulating nestin expression and up‐regulating GFAP expression. These data suggest that populations of parenchymal brain cells, initially expressing both glial and neuronal markers, are capable of differentiating into single neuronal and glial lineages through asymmetric regulation of gene expression in these cells, rather than acquiring markers through differentiation.

Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders.

Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders.

Reactivation of human neurotropic JC virus expressing oncogenic protein in a recurrent glioblastoma multiforme

Examination of the primary tumor of glioblastoma multiforme and its recurrence for their association with JC virus revealed that, while the viral genome is present in both initial and recurrent tumors, expression of the viral oncoprotein T‐antigen occurs only in the recurrent tumor cells. Accordingly, the level of inducible cellular transcription factors, including the p65 subunit of NF‐κB and YB‐1, which have the ability to stimulate JCV gene expression, was found to be higher in the recurrent tumor cells. These observations suggest that induction of the regulatory factors after resection of the primary tumor may have reactivated JC virus gene expression and led to redevelopment of the tumor in brain. Ann Neurol 2000;48:932–936

Pyramidal and extrapyramidal dysfunction as a sequela of hypoxic injury: case report

BackgroundThe clinical and radiological aspects of hypoxic brain injury without ischemia are not well characterized. A spectrum of clinical manifestations have been observed in patients that recover from hypoxic brain injury, including a subset that demonstrate persistent motor system disturbances. Early Magnetic Resonance Imaging (MRI) studies have shown abnormalities in basal ganglia, cerebral and cerebellar cortex.Case presentationA 23-year-old man was affected by acute respiratory failure after drug overdose. His clinical condition progressed from coma to partial recovery with persistent lack of control and stiffness in the lower extremities. MRI of the brain showed evolving lesions in the cerebellum, globus pallidus and motor cortex that correlated with neurological signs.ConclusionA careful analysis of this case and a review of the relevant literature indicate that the clinical residua after recovery from hypoxic injury to the brain is predominantly disorders of the motor system, and the MRI manifestations as well as the clinical presentation can evolve over time. Understanding more of the factors that affect hypoxic brain injury can be helpful in determining the clinical outcome and management of these patients.

Bone marrow-derived mesenchymal stem cells undergo JCV T-antigen mediated transformation and generate tumors with neuroectodermal characteristics.

There is now accumulating evidence showing that some tumors may arise from transformed stem cells. In this study we demonstrate that adult bone marrow- derived mesenchymal stem cells (MSCs) undergo neoplastic transformation induced by the human polyomavirus JCV, early protein, T-antigen, and are tumorigenic when transplanted into the flanks of Nude mice as compared to non-transformed MSCs. Histologically, the tumors are heterogeneous with mesenchymal and neural crest characteristics as evidenced by expression of the neural crest markers p75, SOX-10, and S-100, with populations of tumor cells exhibiting characteristics of primitive neuroectodermal cells. In addition, a subset of T-antigen positive tumor cells exhibit a high proliferation index as detected by Ki-67 labeling, and co-express CD133, a marker which is expressed on cancer stem cells. These results show that tumors with neuroectodermal characteristics may arise from transformation of MSCs, a globally accessible adult stem cell with multipotent differentiation capacity. In light of earlier reports on the association of JCV with a broad variety of human tumors, our data suggests that T-antigen transformation of adult stem cells with a multipotent capacity can serve as a possible common origin for some of these cancers, and offers a novel model for oncogenesis.

Neuronal and astrocytic cells, obtained after differentiation of human neural GFAP-positive progenitors, present heterogeneous expression of PrPc

PrP(c) is a cellular isoform of the prion protein with an unknown normal function. One of the putative physiological roles of this protein is its involvement in cell differentiation. Recently, in vitro and in vivo studies showed that GFAP-positive cells have characteristics of stem/progenitor cells that generate neurons and glia. We used an in vitro model of human neurogenesis from GFAP-positive progenitor cells to study the expression of PrP(c) during neural differentiation. Semi-quantitative multiplex-PCR assay and Western blot analysis revealed a significant increase of PRNP expression level in differentiated cells compared to undifferentiated cell population. As determined by immunocytochemistry followed by a quantitative image analysis, the PrP(c) level increased significantly in neuronal cells and did not increase significantly in glial cells. Of note, glial and neuronal cells showed a very large heterogeneity of PrP(c) expression. Our results provide the basis for studying the role of PrP(c) in cell differentiation and neurogenesis from human GFAP-positive progenitor cells.

A population of human brain cells expressing phenotypic markers of more than one lineage can be induced in vitro to differentiate into mesenchymal cells

Proliferating astrocytic cells from germinal, as well as mature areas of brain parenchyma, have the characteristics of neural stem/progenitor cells and are capable of generating both neurons and glia. We previously reported that primary fetal human brain cells, designated as Normal Human Astrocytes (NHA), expressed, in addition to GFAP, Vimentin and Nestin, low levels of betaIII-Tubulin, an early neuronal marker, and differentiated into neurons and astrocytes in vitro. Here, we showed that primary NHA cells co-express low levels of mesenchymal markers Fibronectin and Collagen-1 in culture. These cells transitioned into mesenchymal-like cells when cultured in adherent conditions in serum containing media. The mesenchymal-like derivatives of these cells were characterized based on their morphological changes, high expression of Vimentin and extracellular matrix (ECM) proteins, Collagen-1 and Fibronectin, and decline of neural markers. When incubated in osteogenic and adipogenic induction media, the mesenchymal-like cells differentiated into osteoblasts and adipocytes. Furthermore, NHA cells express markers of neural crest cells, SOX-10 and p75. These data support the idea of ectoderm-derived mesenchymal lineages. These findings suggest that a population of primitive fetal brain cells with neural/neural crest/mesenchymal phenotype, resembles the remarkable phenotypic plasticity of neural crest cells, and differentiates into adipocytes and osteocytes under the influence of environmental factors.

The spectrum of neuromyelitis optica: a case of NMO with extensive brain stem involvement.

Abstract Neuromyelitis optica (NMO), regarded as a distinct clinical entity from multiple sclerosis (MS), is generally characterized by demyelinating lesions involving optic nerves and spinal cord with sparing of the brain. We report a case with initial clinical, radiological and serological features consistent with NMO, but with concomitant extensively clinical and radiological involvement of the brain stem. Although there are well defined criteria for NMO that restricts the lesions to optic nerves and spinal cord, the case presented here and the review of literature support the idea that NMO may present as a spectrum of clinical and radiological entities rather than the confining clinical criteria that has been hitherto applied.

Intracerebral hemorrhage with intraventricular extension and no hydrocephalus may not increase mortality or severe disability

This paper aimed to test the hypothesis that intraventricular extension of spontaneous intracerebral hemorrhage (ICH) in the absence of hydrocephalus is not associated with increased mortality or severe disability. We performed a retrospective consecutive cohort study of patients with primary spontaneous ICH who were admitted to a single institution. Multivariate logistic regression analysis was used to assess the association of each variable with functional outcome as measured by the modified Rankin Scale (mRS). A total of 164 patients met our inclusion criteria and were included in the study. Only hydrocephalus (p=0.002) and hematoma volume (p=0.006) were significantly associated with mortality or poor functional outcome (mRS of 3 to 6). In contrast, the presence of intraventricular hematoma was not independently associated with poor functional outcome. The presence of intraventricular extension of ICH in the absence of hydrocephalus may not increase mortality or disability.

Brain to music to brain

It has been implicitly understood that culture and music as collective products of human brain in turn influence the brain itself. Now, imaging and anatomical data add substance to this notion. The impact of playing piano on the brain of musicians and its possible effects on cultural and neurological evolution are briefly discussed.