Dong Hyuk Park

Transplantation of Umbilical Cord Blood Stem Cells for Treating Spinal Cord Injury

Spinal cord injury (SCI) develops primary and secondary damage to neural tissue and this often results in permanent disability of the motor and sensory functions. However, there is currently no effective treatment except methylprednisolone, and the use of methylprednisolone has also been questioned due to its moderate efficacy and the drug’s downside. Regenerative medicine has remarkably developed since the discovery of stem cells, and many studies have suggested the potential of cell-based therapies for neural injury. Especially, the therapeutic potential of human umbilical cord blood cells (hUCB cells) for intractable neurological disorders has been demonstrated using in vitro and vivo models. The hUCB cells are immune naïve and they are able to differentiate into other phenotypes, including the neural lineage. Their ability to produce several neurotropic factors and to modulate immune and inflammatory reactions has also been noted. Recent evidence has emerged suggesting alternative pathways of graft-mediated neural repair that involve neurotrophic effects. These effects are caused by the release of various growth factors that promote cell survival, angiogenesis and anti-inflammation, and this is all aside from a cell replacement mechanism. In this review, we present the recent findings on the stemness properties and the therapeutic potential of hUCB as a safe, feasible and effective cellular source for transplantation in SCI. These multifaceted protective and restorative effects from hUCB grafts may be interdependent and they act in harmony to promote therapeutic benefits for SCI. Nevertheless, clinical studies with hUCB are still rare because of the concerns about safety and efficiency. Among these concerns, the major histocompatibility in allogeneic transplantation is an important issue to be addressed in future clinical trials for treating SCI.

Increased Neuronal Proliferation in the Dentate Gyrus of Aged Rats Following Neural Stem Cell Implantation

It is now well accepted that the brain is able to generate newborn neurons from a population of resident multipotential neural stem cells (NSCs) located in two discrete regions of the brain. The capacity for neurogenesis appears to diminish over the lifespan of an organism. Methods to potentiate the proliferation of new neuronal or glial cells within the central nervous system from resident NSCs could have therapeutic potential following an insult, such as stroke, or to replace lost cells as a result of a neurodegenerative disease. We implanted cells from a human NSC cell line, CTX0E03, originally derived from fetal cortical tissue directly into the ventricles of aged rats. CTX0E03 cells have angiogenic properties via secretion of growth factors, so we investigated if the implanted cells would stimulate proliferation of NSCs within the subgranular zone (SGZ) of the dentate gyrus. Bromodeoxyuridine staining demonstrated significantly increased proliferation in the SGZ. Absence of double labeling for human nuclear antigen suggested that the increased proliferation was from endogenous neural progenitor cells. The acute treatment also led to an increased number of immature neurons as demonstrated by immunohistochemical staining for the immature neuronal marker doublecortin. The data suggest that implants of exogenous NSCs may promote regeneration in aging organisms through stimulation of endogenous neurogenesis.

Customized Cranioplasty Implants Using Three-Dimensional Printers and Polymethyl-Methacrylate Casting

Objective The prefabrication of customized cranioplastic implants has been introduced to overcome the difficulties of intra-operative implant molding. The authors present a new technique, which consists of the prefabrication of implant molds using three-dimensional (3D) printers and polymethyl-methacrylate (PMMA) casting. Methods A total of 16 patients with large skull defects (>100 cm2) underwent cranioplasty between November 2009 and April 2011. For unilateral cranial defects, 3D images of the skull were obtained from preoperative axial 1-mm spiral computed tomography (CT) scans. The image of the implant was generated by a digital subtraction mirror-imaging process using the normal side of the cranium as a model. For bilateral cranial defects, precraniectomy routine spiral CT scan data were merged with postcraniectomy 3D CT images following a smoothing process. Prefabrication of the mold was performed by the 3D printer. Intraoperatively, the PMMA implant was created with the prefabricated mold, and fit into the cranial defect. Results The median operation time was 184.36±26.07 minutes. Postoperative CT scans showed excellent restoration of the symmetrical contours and curvature of the cranium in all cases. The median follow-up period was 23 months (range, 14-28 months). Postoperative infection was developed in one case (6.2%) who had an open wound defect previously. Conclusion Customized cranioplasty PMMA implants using 3D printer may be a useful technique for the reconstruction of various cranial defects.

Activated STAT3 regulates hypoxia-induced angiogenesis and cell migration in human glioblastoma.

BACKGROUND:Glioblastoma is the most common primary brain tumor, with typical histopathologic findings, pseudopalisading necrosis, and microvascular proliferation, all of which are associated with a poor prognosis. Hypoxia is known to affect these morphological features, but the underlying molecular mechanism has been poorly understood. OBJECTIVE:To determine the role of signal transducer and activator of transcription 3 (STAT3) in the malignant progression of glioblastoma under hypoxic conditions. METHODS:We studied STAT3 activation by hypoxic stress and its effect on hypoxia-induced angiogenesis and cell migration using U87, A172, T98, and U373 human glioblastoma cell lines. RESULTS:All four glioblastoma cells analyzed expressed detectable levels of STAT3 phosphorylation. Hypoxic stress markedly increased phosphorylated STAT3 level in a time-dependent fashion, and activated STAT3 was translocated into the nucleus. Hypoxic conditions led to a 30-50% increase in angiogenesis and cell migration, but these effects were significantly attenuated by small interfering ribonucleic acid-mediated knockdown of STAT3. Furthermore, STAT3 activation was associated with an elevated expression of hypoxic inducible factor-1, vascular endothelial growth factor, matrix metalloproteinase 2, and TWIST messenger ribonucleic acid and protein, which may play a critical role in hypoxia-induced angiogenesis and migration. CONCLUSION:STAT3 plays an important role in glioblastoma angiogenesis and migration triggered by hypoxia. Therefore, STAT3 might be a target for control of pseudopalisading necrosis and angiogenesis in glioblastoma.

Monocyte transplantation for neural and cardiovascular ischemia repair.

•  Introduction •  Role of monocyte in neovascularization ‐  Angiogenesis in ischemia ‐  Angiogenesis in tumour and chronic inflammation •  Monocytes versus stem cells for transplantation ‐  Monocytes from umbilical cord blood •  Conclusions

Mankind’s first natural stem cell transplant

•  Introduction •  Early haematopoiesis in foetus •  Early versus late clamping of the umbilical cord •  Stem cells in human umbilical cord blood ‐  Cellular composition ‐  Usefulness of umbilical cord blood stem cells •  First stem cell transplantation at birth •  Conclusions

Angiographic features, surgical management and outcomes of proximal middle cerebral artery aneurysms

OBJECTIVE Understanding the microanatomy of the proximal middle cerebral artery (M1) and its early branches is very important for aneurysm surgery in this region. However, few articles provide detailed descriptions of such aneurysms. We report the angiographic characteristics of a series of M1 aneurysms and our experience with M1 aneurysm surgery. MATERIALS AND METHODS Twenty-three patients with 25 (combined) M1 aneurysms presented to our institution from January 2001 to December 2006. We examined the general characteristics and angiographic features of the M1 aneurysms, such as site, size, direction, and their association with early branches. RESULTS Of the 23 patients with M1 aneurysms, 13 were women and 10 were men. Nineteen of the aneurysms had ruptured prior to presentation. Multiple aneurysms were observed in 10 of the patients. Angiography showed that 14 of the aneurysms were less than 5mm in size, and most of the aneurysmal projections were superior. Eighteen of the aneurysms involved early frontal branches and three involved the lenticulostriate arteries. Postoperative infarction was seen in eight patients. Five of the eight patients showed either no or slight neurological deficits at the follow-up visit. One patient, however, suffered from hemiparesis and aphasia that corresponded to the vascular territory of the early frontal branches and lenticulostriate arteries. Two patients had a total MCA infarction and a posterior fossa infarction, respectively. CONCLUSIONS This study highlights the need for the critical management of M1 aneurysms, taking into consideration the size and number of aneurysms. By performing careful angiographic investigation of the aneurysm and related early arterial branches of M1, postoperative complications may be minimized.

Oncocytic paraganglioma of the cauda equina in a child: Case report and review of the literature

The authors report a case of oncocytic paraganglioma of the cauda equina in a 12-year-old girl who presented with lower back and leg pain on the right side of 6 months’ duration. Magnetic resonance imaging revealed an ellipsoidal, intradural, extramedullary mass causing cord compression at the level of L1. Total laminectomy was performed on T12 and L1, and the tumor was excised completely without difficulty despite adherence of the tumor to the spinal cord. Postoperatively, the leg pain and motor weakness were much improved. The use of electron microscopy, and the immunohistochemical demonstration of synaptophysin in this tumor, allowed a confident diagnosis of an oncocytic paraganglioma to be made. To the authors’ knowledge, this patient represents the first definite case of an oncocytic paraganglioma of the cauda equina in a child.

Reactive oxygen species production has a critical role in hypoxia-induced Stat3 activation and angiogenesis in human glioblastoma

Glioblastoma is the most aggressive primary brain tumor with hypoxia-associated morphologic features including pseudopalisading necrosis and endothelial hyperplasia. It has been known that hypoxia can activate signal transducer and activator of transcription 3 (Stat3) and subsequently induce angiogenesis. However, the molecular mechanism underlying hypoxia-induced Stat3 activation has not been defined. In this study, we explored the possible implication of reactive oxygen species (ROS) in hypoxia-driven Stat3 activation in human glioblastoma. We found that hypoxic stress increased ROS production as well as Stat3 activation and that ROS inhibitors (diphenyleneiodonium, rotenone and myxothiazol) and an antioxidant (N-acetyl-l-cysteine) blocked Stat3 activation under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is involved in hypoxia-induced ROS production. Nox4 expression was found to be increased at both mRNA and protein levels in hypoxic glioblastoma cells. In addition, siRNA-mediated knockdown of Nox4 expression abolished hypoxia induced Stat3 activation and vascular endothelial growth factor expression, which is associated with tumor cells’ ability to trigger tube formation of endothelial cells in vitro. Our findings indicate that elevated ROS production plays a crucial role for Stat3 activation and angiogenesis in hypoxic glioblastoma cells.

Comparison of cerebrospinal fluid biomarkers between idiopathic normal pressure hydrocephalus and subarachnoid hemorrhage-induced chronic hydrocephalus: A pilot study

Summary Background We examined the cerebrospinal fluid (CSF) markers of subarachnoid hemorrhage (SAH)-induced and idiopathic normal pressure hydrocephalus (INPH) to investigate the pathophysiology and mechanism of communicating hydrocephalus compared to obstructive hydrocephalus. Material/Methods We obtained CSF samples from 8 INPH, 10 SAH-induced hydrocephalus, and 6 unmatched patients with non-hemorrhagic obstructive hydrocephalus during their ventriculoperitoneal shunt operations. Transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and total tau in the CSF were analyzed via enzyme-linked immunosorbent assay. Results The mean VEGF levels in the CSF of patients with SAH-induced hydrocephalus, INPH, and obstructive hydrocephalus were 239±131, 239±75, and 163±122 pg/mL, respectively. The total tau concentrations in the CSF of the groups were 1139±1900, 325±325, and 1550±2886 pg/mL, respectively. TNF-α values were 114±34, 134±38, and 55±16 pg/mL, respectively. TGF-β1 values were 953±430, 869±447, and 136±63 pg/mL, respectively. A significant difference in TNF-α and TGF-β1 levels was observed only between SAH-induced and chronic obstructive hydrocephalus, and between INPH and chronic obstructive hydrocephalus (p<0.01). Conclusions No significant differences in the 4 CSF biomarker levels were observed between INPH and SAH-induced hydrocephalus, whereas CSF TNF-α and TGF-β1 levels were increased compared to those in patients with chronic obstructive hydrocephalus. Post-SAH hydrocephalus and INPH are probably more destructive to neural tissues, and then stimulate the inflammatory reaction and healing process, compared with obstructive hydrocephalus.