Takuro Kojima

Subventricular Zone-Derived Neuroblasts Migrate and Differentiate into Mature Neurons in the Post-Stroke Adult Striatum

Recent studies have revealed that the adult mammalian brain has the capacity to regenerate some neurons after various insults. However, the precise mechanism of insult-induced neurogenesis has not been demonstrated. In the normal brain, GFAP-expressing cells in the subventricular zone (SVZ) of the lateral ventricles include a neurogenic cell population that gives rise to olfactory bulb neurons only. Herein, we report evidence that, after a stroke, these cells are capable of producing new neurons outside the olfactory bulbs. SVZ GFAP-expressing cells labeled by a cell-type-specific viral infection method were found to generate neuroblasts that migrated toward the injured striatum after middle cerebral artery occlusion. These neuroblasts in the striatum formed elongated chain-like cell aggregates similar to those in the normal SVZ, and these chains were observed to be closely associated with thin astrocytic processes and blood vessels. Finally, long-term tracing of the green fluorescent-labeled cells with a Cre-loxP system revealed that the SVZ-derived neuroblasts differentiated into mature neurons in the striatum, in which they expressed neuronal-specific nuclear protein and formed synapses with neighboring striatal cells. These results highlight the role of the SVZ in neuronal regeneration after a stroke and its potential as an important therapeutic target for various neurological disorders.

Subventricular Zone-Derived Neural Progenitor Cells Migrate Along a Blood Vessel Scaffold Toward the Post-stroke Striatum

The subventricular zone (SVZ) of the adult brain contains neural stem cells that have the capacity to regenerate new neurons after various insults. Brain ischemia causes damage to brain tissue and induces neural regeneration together with angiogenesis. We previously reported that, after ischemic injury in mice, SVZ‐derived neural progenitor cells (NPCs) migrate into the striatum, and these NPCs are frequently associated with blood vessels in the regenerating brain tissue. Here we studied the role of blood vessels during the neural regeneration in more detail. BrdU administration experiments revealed that newly generated NPCs were associated with both newly formed and pre‐existing blood vessels in the ischemic striatum, suggesting that the angiogenic environment is not essential for the neuron‐blood vessel interaction. To observe migrating NPCs and blood vessels simultaneously in damaged brain tissue, we performed live imaging of cultured brain slices after ischemic injury. In this system, we virally labeled SVZ‐derived NPCs in Flk1‐EGFP knock‐in mice in which the blood vessels are labeled with EGFP. Our results provide direct evidence that SVZ‐derived NPCs migrate along blood vessels from the SVZ toward the ischemic region of the striatum. The leading process of the migrating NPCs was closely associated with blood vessels, suggesting that this interaction provides directional guidance to the NPCs. These findings suggest that blood vessels play an important role as a scaffold for NPCs migration toward the damaged brain region. STEM CELLS 2010;28:545–554

Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain

Neural stem/progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes, and oligodendrocytes. It has become apparent that intracellular epigenetic modification including DNA methylation, in concert with extracellular cues such as cytokine signaling, is deeply involved in fate specification of NSCs/NPCs by defining cell-type specific gene expression. However, it is still unclear how differentiated neural cells retain their specific attributes by repressing cellular properties characteristic of other lineages. In previous work we have shown that methyl-CpG binding protein transcriptional repressors (MBDs), which are expressed predominantly in neurons in the central nervous system, inhibit astrocyte-specific gene expression by binding to highly methylated regions of their target genes. Here we report that oligodendrocytes, which do not express MBDs, can transdifferentiate into astrocytes both in vitro (cytokine stimulation) and in vivo (ischemic injury) through the activation of the JAK/STAT signaling pathway. These findings suggest that differentiation plasticity in neural cells is regulated by cell-intrinsic epigenetic mechanisms in collaboration with ambient cell-extrinsic cues.

Marked disparity in mechanical wall properties between ascending and descending aorta in patients with tetralogy of Fallot

OBJECTIVES Recent studies have linked abnormal aortic medial pathology to progressive aortic root dilatation in patients with tetralogy of Fallot (TOF). To explore whether the aortic medial pathology in TOF is linked to aortic mechanical property, the present study tested the hypothesis that the distribution of impaired aortic elasticity corresponds to the known distribution of abnormal medial pathology (confined to the ascending aorta) in TOF. METHODS Pulse wave velocity (PWV) of the proximal and distal aortas was measured with a high-fidelity micromanometer in 98 TOF patients (64 with repaired TOF and 34 with unrepaired TOF) and 63 control subjects. RESULTS PWV of the proximal aorta was significantly higher in TOF than in the control, but similar in repaired and unrepaired TOF (repaired: 588 ± 205 cm/s, unrepaired: 680 ± 288 cm/s, control: 439 ± 101 cm/s, P < 0.001 for each TOF group vs. control, P = 0.07 for repaired vs. unrepaired TOF). In contrast, PWV of the distal aorta was almost identical among the three groups (repaired: 441 ± 189 cm/s, unrepaired: 430 ± 114 cm/s, control: 461 ± 164 cm/s, P = 0.73, analysis of variance), indicating that abnormal aortic mechanical property is confined to the proximal aorta regardless of the operative status of TOF. This was also confirmed by comparison within the group; PWV of the proximal aorta was significantly higher than that of the distal aorta in both TOF groups (P < 0.001, each), whereas there was no difference in PWV between the proximal and distal aortas in the control subjects (P = 0.61). CONCLUSIONS Consistent with the known histopathological disparity between the media of the ascending and descending aortas, aortic stiffness is markedly increased in the proximal but not in the distal aorta of TOF. These results suggest that aortic wall stiffness is a potentially useful clinical marker of aortic dilation in patients with TOF.

Clostridium difficile colitis induced by long-term low-dosage erythromycin.

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Successful radiofrequency catheter ablation of life-threatening atrial tachycardia in an infant with asplenia syndrome

A 1-year-old infant with asplenia syndrome and congenital heart disease consisting of common atrium, common inlet left ventricle with a common atrio-ventricular (AV) valve, pulmonary atresia, and total anomalous pulmonary venous connection was admitted to our hospital for radiofrequency catheter ablation (RFCA) of supraventricular tachycardia (SVT) before total cavo-pulmonary connection. After antiarrhythmic medications were discontinued for RFCA, she suffered from SVT that resulted in the rapid deterioration of hemodynamic status. Antiarrhythmic medications and cardioversion were not effective in terminating SVT. The baseline electrocardiogram confirmed the existence of twin AV nodes; however, this SVT was revealed to be focal atrial tachycardia (AT) with enhanced automaticity. The origin of AT was not related to surgical scar. Emergent RFCA for AT was successful in our case of asplenia syndrome. AT is a life-threatening complication in a single ventricle and delayed treatment can be fatal. It is important to perform RFCA promptly when drug treatment is not effective. We suggest that the AV node is not always the target site for ablation in patients with asplenia syndrome and twin AV nodes. <Learning objective: In the case of supraventricular tachycardia with asplenia and twin atrio-ventricular (AV) nodes, atrial tachycardia (AT) as well as AV reentrant tachycardia could occur. AT is a life-threatening complication in infants with single ventricle. If drug therapy is not effective, emergent catheter ablation should be performed. AV node is not always the target site for ablation in patients with asplenia and twin AV nodes.>.

Successful emergent coil embolization of an inferior epigastric artery perforation in a neonate

A 28-day-old neonate with a postoperative ventricular septal defect and coarctation of aorta suffered from a right inferior epigastric artery perforation at the time of a central venous catheter placement. It resulted in a rapid and extreme hemoglobin decrease and decrease in the systolic blood pressure. The contrast computed tomography scan revealed a large amount of retroperitoneal hemorrhaging and a hematoma. Pressure hemostasis was not effective in eliminating the extravasation and surgical hemostasis seemed uncertain to succeed, because the baby was too small and its condition was unstable. An emergent coil embolization using a Target® coil (Stryker Inc., Tokyo, Japan) was effective in completely eliminating the extravasation, resulting in saving its life. We speculated that a coil embolization was the only solution to rescue a neonate with a retroperitoneal hemorrhage due to an artery perforation. <Learning objective: Retroperitoneal hemorrhaging caused by an inferior epigastric artery perforation is a fatal condition in a neonate, because the neonate cannot express symptoms and this results in a delay in diagnosing it. Pressure hemostasis and surgical hemostasis are not effective in these cases. If a peritoneal hemorrhage is suspected, a coil embolization must be performed promptly as a sole solution to rescue the patient.>.