Skip to content
Articles by Sung-Rae Cho in JoVE
-
Neurobehavioral vurderinger i en musemodell av Neonatal Hypoxic-iskemisk hjerneskade
MinGi Kim1,2, Ji Hea Yu1, Jung Hwa Seo1,2, Yoon-Kyum Shin1,2, Soohyun Wi1,2, Ahreum Baek1,3, Suk-Young Song1,5, Sung-Rae Cho1,2,4,5
1Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, 2Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 3Department of Rehabilitation Medicine, Yonsei University Wonju College of Medicine, 4Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, 5Graduate Program of NanoScience and Technology, Yonsei University
Vi utførte ensidige arteria carotis okklusjon postnatal dag 7-10 CD-1 mus pups å opprette en neonatal hypoxic-iskemiske (HI) modell og undersøkt virkningene av HI hjerneskade. Vi studerte neurobehavioral funksjoner i disse musene sammenlignet med ikke-opererte normal mus.
Other articles by Sung-Rae Cho on PubMed
-
-
-
-
-
-
-
-
-
-
Highly Pure and Expandable PSA-NCAM-positive Neural Precursors from Human ESC and IPSC-derived Neural Rosettes
PloS One.
|
Pubmed ID: 22911689 Homogeneous culture of neural precursor cells (NPCs) derived from human pluripotent stem cells (hPSCs) would provide a powerful tool for biomedical applications. However, previous efforts to expand mechanically dissected neural rosettes for cultivation of NPCs remain concerns regarding non-neural cell contamination. In addition, several attempts to purify NPCs using cell surface markers have not demonstrated the expansion capability of the sorted cells. In the present study, we show that polysialic acid-neural cell adhesion molecule (PSA-NCAM) is detected in neural rosette cells derived from hPSCs, and employ PSA-NCAM as a marker for purifying expandable primitive NPCs from the neural rosettes. PSA-NCAM-positive NPCs (termed hNPC(PSA-NCAM+)) were isolated from the heterogeneous cell population of mechanically harvested neural rosettes using magnetic-based cell sorting. The hNPC(PSA-NCAM+) extensively expressed neural markers such as Sox1, Sox2, Nestin, and Musashi-1 (80∼98% of the total cells) and were propagated for multiple passages while retaining their primitive characteristics in our culture condition. Interestingly, PSA-NCAM-negative cells largely exhibited characteristics of neural crest cells. The hNPC(PSA-NCAM+) showed multipotency and responsiveness to instructive cues towards region-specific neuronal subtypes in vitro. When transplanted into the rat striatum, hNPC(PSA-NCAM+) differentiated into neurons, astrocytes, and oligodendrocytes without particular signs of tumorigenesis. Furthermore, Ki67-positive proliferating cells and non-neural lineage cells were rarely detected in the grafts of hNPC(PSA-NCAM+) compared to those of neural rosette cells. Our results suggest that PSA-NCAM-mediated cell isolation provides a highly expandable population of pure primitive NPCs from hPSCs that will lend themselves as a promising strategy for drug screening and cell therapy for neurodegenerative disorders.
-
Neurorestoration Induced by Mesenchymal Stem Cells: Potential Therapeutic Mechanisms for Clinical Trials
Yonsei Medical Journal.
|
Pubmed ID: 23074102 Stem cells are emerging as therapeutic candidates in a variety of diseases because of their multipotent capacities. Among these, mesenchymal stem cells (MSCs) derived from bone marrow, umbilical cord blood or adipose tissue, comprise a population of cells that exhibit extensive proliferative potential and retain the ability to differentiate into multiple tissue-specific lineage cells including osteoblasts, chondrocytes, and adipocytes. MSCs have also been shown to enhance neurological recovery, although the therapeutic effects seem to be derived from an indirect paracrine effect rather than direct cell replacement. MSCs secrete neurotrophic factors, promote endogenous neurogenesis and angiogenesis, encourage synaptic connection and remyelination of damaged axons, decrease apoptosis, and regulate inflammation primarily through paracrine actions. Accordingly, MSCs may prevail as a promising cell source for cell-based therapy in neurological diseases.
-
-
Environmental Enrichment Synergistically Improves Functional Recovery by Transplanted Adipose Stem Cells in Chronic Hypoxic-ischemic Brain Injury
Cell Transplantation.
|
Pubmed ID: 23394350 We investigated the effects of environmental enrichment (EE) on the function of transplanted adipose stem cells (ASCs) and the combined effect of EE and ASC transplantation on neurobehavioral function in an animal model of chronic hypoxic-ischemic (HI) brain injury. HI brain damage was induced in 7-day-old mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min). At 6 weeks of age, the mice were randomly injected with either ASCs or PBS into the striatum and were randomly assigned to either EE or standard cages (SC), comprising ASC-EE (n=18), ASC-SC (n=19), PBS-EE (n=12), PBS-SC (n=17), and untreated controls (n=23). Rotarod, forelimb-use asymmetry, and grip strength tests were performed to evaluate neurobehavioral function. The fate of transplanted cells and the levels of endogenous neurogenesis, astrocyte activation, and paracrine factors were also measured. As a result, EE and ASC transplantation synergistically improved rotarod latency, forelimb-use asymmetry, and grip strength compared to those of the other groups. The number of engrafted ASCs and βIII-tubulin(+) neurons derived from the transplanted ASCs was significantly higher in mice in EE than those in SC. EE and ASC transplantation also synergistically increased BrdU(+)βIII-tubulin(+) neurons, GFAP(+) astrocytic density, and fibroblast growth factor 2 (FGF2) level but not the level of CS-56(+) glial scarring in the striatum. In conclusion, EE and ASC transplantation synergistically improved neurobehavioral functions. The underlying mechanisms of this synergism included enhanced repair processes such as higher engraftment of the transplanted ASCs, increased endogenous neurogenesis and astrocytic activation coupled with upregulation of FGF2.
-
Acoustic Characteristics of Vowel Sounds in Patients with Parkinson Disease
NeuroRehabilitation.
|
Pubmed ID: 23648619 The purpose of this study was to define the acoustic voice and speech characteristics of patients with Parkinson disease (PD). Seven female patients with PD and seven female healthy controls participated in this study. Each subject was instructed to vocalize extended corner vowels (/a/, /e/, /i/, /u/) three times for at least 5 seconds at a comfortable voice loudness and tone. The voice was analyzed using the Praat program. As a result, female patients with PD showed a significant increase in jitter and noise-to-harmonics ratio (NHR). In addition, F1 and F2 among the PD patients demonstrated asymmetric centralization of unrounded vowels (/a/, /e/, /i/) in high/low/front/back positions of the tongue, consequently leading to a significant decrease in vowel space area, compared to healthy controls. This study showed the acoustic characteristics of vowel sounds not only by laryngeal variables such as abnormal jitter and NHR, but also by articulatory variables such as asymmetric centralization and reduced vowel space area in female patients with PD. Therefore, it is important to use these objective and sensitive variables to evaluate the status or severity of hypokinetic dysarthria in patients with PD.
-
Therapeutic Effects of Repetitive Transcranial Magnetic Stimulation in an Animal Model of Parkinson's Disease
Brain Research.
|
Pubmed ID: 23998987 Repetitive transcranial magnetic stimulation (rTMS) is used to treat neurological diseases such as stroke and Parkinson's disease (PD). Although rTMS has been used clinically, its underlying therapeutic mechanism remains unclear. The objective of the present study was to clarify the neuroprotective effect and therapeutic mechanism of rTMS in an animal model of PD. Adult Sprague-Dawley rats were unilaterally injected with 6-hydroxydopamine (6-OHDA) into the right striatum. Rats with PD were then treated with rTMS (circular coil, 10 Hz, 20 min/day) daily for 4 weeks. Behavioral assessments such as amphetamine-induced rotational test and treadmill locomotion test were performed, and the dopaminergic (DA) neurons of substantia nigra pas compacta (SNc) and striatum were histologically examined. Expression of neurotrophic/growth factors was also investigated by multiplex ELISA, western blotting analysis and immunohistochemistry 4 weeks after rTMS application. Among the results, the number of amphetamine-induced rotations was significantly lower in the rTMS group than in the control group at 4 weeks post-treatment. Treadmill locomotion was also significantly improved in the rTMS-treated rats. Tyrosine hydroxylase-positive DA neurons and DA fibers in rTMS group rats were greater than those in untreated group in both ipsilateral SNc and striatum, respectively. The expression levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, platelet-derived growth factor, and vascular endothelial growth factor were elevated in both the 6-OHDA-injected hemisphere and the SNc of the rTMS-treated rats. In conclusion, rTMS treatment improved motor functions and survival of DA neurons, suggesting that the neuroprotective effect of rTMS treatment might be induced by upregulation of neurotrophic/growth factors in the PD animal model.
-
-
Fibroblast Growth Factor-2 Induced by Enriched Environment Enhances Angiogenesis and Motor Function in Chronic Hypoxic-ischemic Brain Injury
PloS One.
|
Pubmed ID: 24098645 This study aimed to investigate the effects of enriched environment (EE) on promoting angiogenesis and neurobehavioral function in an animal model of chronic hypoxic-ischemic (HI) brain injury. HI brain damage was induced in seven day-old CD-1® mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min). At six weeks of age, the mice were randomly assigned to either EE or standard cages (SC) for two months. Rotarod, forelimb-use asymmetry, and grip strength tests were performed to evaluate neurobehavioral function. In order to identify angiogenic growth factors regulated by EE, an array-based multiplex ELISA assay was used to measure the expression in frontal cortex, striatum, and cerebellum. Among the growth factors, the expression of fibroblast growth factor-2 (FGF-2) was confirmed using western blotting. Platelet endothelial cell adhesion molecule-1 (PECAM-1) and α-smooth muscle actin (α-SMA) were also evaluated using immunohistochemistry. As a result, mice exposed to EE showed significant improvements in rotarod and ladder walking performances compared to SC controls. The level of FGF-2 was significantly higher in the frontal cortex of EE mice at 8 weeks after treatment in multiplex ELISA and western blot. On the other hand, FGF-2 in the striatum significantly increased at 2 weeks after exposure to EE earlier than in the frontal cortex. Expression of activin A was similarly upregulated as FGF-2 expression pattern. Particularly, all animals treated with FGF-2 neutralizing antibody abolished the beneficial effect of EE on motor performance relative to mice not given anti-FGF-2. Immunohistochemistry showed that densities of α-SMA(+) and PECAM-1(+) cells in frontal cortex, striatum, and hippocampus were significantly increased following EE, suggesting the histological findings exhibit a similar pattern to the upregulation of FGF-2 in the brain. In conclusion, EE enhances endogenous angiogenesis and neurobehavioral functions mediated by upregulation of FGF-2 in chronic hypoxic-ischemic brain injury.
-
-
-
Time-dependent Effect of Combination Therapy with Erythropoietin and Granulocyte Colony-stimulating Factor in a Mouse Model of Hypoxic-ischemic Brain Injury
Neuroscience Bulletin.
|
Pubmed ID: 24435306 Erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) are likely to play broad roles in the brain. We investigated the effects of combination therapy with EPO and G-CSF in hypoxic-ischemic brain injury during the acute, subacute, and chronic phases. A total of 79 C57BL/6 mice with hypoxic-ischemic brain injury were randomly assigned acute (days 1-5), subacute (days 11-15) and chronic (days 28-32) groups. All of them were treated with G-CSF (250 μg/kg) and EPO (5000 U/kg) or saline daily for 5 consecutive days. Behavioral assessments and immunohistochemistry for angiogenesis, neurogenesis, and astrogliosis were performed with an 8-week follow-up. Hypoxia-inducible factor-1 (HIF-1) was also measured by Western blot analysis. The results showed that the combination therapy with EPO and G-CSF in the acute phase significantly improved rotarod performance and forelimb-use symmetry compared to the other groups, while subacute EPO and G-CSF therapy exhibited a modest improvement compared with the chronic saline controls. The acute treatment significantly increased the density of CD31(+) (PECAM-1) and α-smooth muscle actin(+) vessels in the frontal cortex and striatum, increased BrdU(+)/PSA-NCAM(+) neurogenesis in the subventricular zone, and decreased astroglial density in the striatum. Furthermore, acute treatment significantly increased the HIF-1 expression in the cytosol and nucleus, whereas chronic treatment did not change the HIF-1 expression, consistent with the behavioral outcomes. These results indicate that the induction of HIF-1 expression by combination therapy with EPO and G-CSF synergistically enhances not only behavioral function but also neurogenesis and angiogenesis while decreasing the astroglial response in a time-dependent manner.
-
-
-
PSA-NCAM(+) Neural Precursor Cells from Human Embryonic Stem Cells Promote Neural Tissue Integrity and Behavioral Performance in a Rat Stroke Model
Stem Cell Reviews.
|
Pubmed ID: 24974101 Recently, cell-based therapy has been highlighted as an alternative to treating ischemic brain damage in stroke patients. The present study addresses the therapeutic potential of polysialic acid-neural cell adhesion molecule (PSA-NCAM)-positive neural precursor cells (NPC(PSA-NCAM+)) derived from human embryonic stem cells (hESCs) in a rat stroke model with permanent middle cerebral artery occlusion. Data showed that rats transplanted with NPC(PSA-NCAM+) are superior to those treated with phosphate buffered saline (PBS) or mesenchymal stem cells (MSCs) in behavioral performance throughout time points. In order to investigate its underlying events, immunohistochemical analysis was performed on rat ischemic brains treated with PBS, MSCs, and NPC(PSA-NCAM+). Unlike MSCs, NPC(PSA-NCAM+) demonstrated a potent immunoreactivity against human specific nuclei, doublecortin, and Tuj1 at day 26 post-transplantation, implying their survival, differentiation, and integration in the host brain. Significantly, NPC(PSA-NCAM+) evidently lowered the positivity of microglial ED-1 and astrocytic GFAP, suggesting a suppression of adverse glial activation in the host brain. In addition, NPC(PSA-NCAM+) elevated α-SMA(+) immunoreactivity and the expression of angiopoietin-1 indicating angiogenic stimulation in the host brain. Taken together, the current data demonstrate that transplanted NPC(PSA-NCAM+) preserve brain tissue with reduced infarct size and improve behavioral performance through actions encompassing anti-reactive glial activation and pro-angiogenic activity in a rat stroke model. In conclusion, the present findings support the potentiality of NPC(PSA-NCAM+) as the promising source in the development of cell-based therapy for neurological diseases including ischemic stroke.
-
-
-
-
-
Effects of Low- and High-frequency Repetitive Magnetic Stimulation on Neuronal Cell Proliferation and Growth Factor Expression: A Preliminary Report
Neuroscience Letters.
|
Pubmed ID: 26235239 Repetitive magnetic stimulation is a neuropsychiatric and neurorehabilitation tool that can be used to investigate the neurobiology of sensory and motor functions. Few studies have examined the effects of repetitive magnetic stimulation on the modulation of neurotrophic/growth factors and neuronal cells in vitro. Therefore, the current study examined the differential effects of repetitive magnetic stimulation on neuronal cell proliferation as well as various growth factor expression. Immortalized mouse neuroblastoma cells were used as the cell model in this study. Dishes of cultured cells were randomly divided into control, sham, low-frequency (0.5Hz, 1Tesla) and high-frequency (10Hz, 1Tesla) groups (n=4 dishes/group) and were stimulated for 3 days. Expression of neurotrophic/growth factors, Akt and Erk was investigated by Western blotting analysis 3 days after repetitive magnetic stimulation. Neuroblastoma cell proliferation was determined with a cell counting assay. There were differences in cell proliferation based on stimulus frequency. Low-frequency stimulation did not alter proliferation relative to the control, while high-frequency stimulation elevated proliferation relative to the control group. The expression levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and platelet-derived growth factor (PDGF) were elevated in the high-frequency magnetic stimulation group. Akt and Erk expression was also significantly elevated in the high-frequency stimulation group, while low-frequency stimulation decreased the expression of Akt and Erk compared to the control. In conclusion, we determined that different frequency magnetic stimulation had an influence on neuronal cell proliferation via regulation of Akt and ERK signaling pathways and the expression of growth factors such as BDNF, GDNF, NT-3 and PDGF. These findings represent a promising opportunity to gain insight into how different frequencies of repetitive magnetic stimulation may mediate cell proliferation.
-
-
-
-
Induction of Neurorestoration From Endogenous Stem Cells
Cell Transplantation.
|
Pubmed ID: 26787093 Neural stem cells (NSCs) persist in the subventricular zone lining the ventricles of the adult brain. The resident stem/progenitor cells can be stimulated in vivo by neurotrophic factors, hematopoietic growth factors, magnetic stimulation, and/or physical exercise. In both animals and humans, the differentiation and survival of neurons arising from the subventricular zone may also be regulated by the trophic factors. Since stem/progenitor cells present in the adult brain and the production of new neurons occurs at specific sites, there is a possibility for the treatment of incurable neurological diseases. It might be feasible to induce neurogenesis, which would be particularly efficacious in the treatment of striatal neurodegenerative conditions such as Huntington's disease, as well as cerebrovascular diseases such as ischemic stroke and cerebral palsy, conditions that are widely seen in the clinics. Understanding of the molecular control of endogenous NSC activation and progenitor cell mobilization will likely provide many new opportunities as therapeutic strategies. In this review, we focus on endogenous stem/progenitor cell activation that occurs in response to exogenous factors including neurotrophic factors, hematopoietic growth factors, magnetic stimulation, and an enriched environment. Taken together, these findings suggest the possibility that functional brain repair through induced neurorestoration from endogenous stem cells may soon be a clinical reality.
-
Early Immunomodulation by Intravenously Transplanted Mesenchymal Stem Cells Promotes Functional Recovery in Spinal Cord Injured Rats
Cell Medicine.
|
Pubmed ID: 26998402 Although intravenous administration of mesenchymal stem cells (MSCs) can enhance functional recovery after spinal cord injury (SCI), the underlying mechanisms have to be elucidated. In this study, we explored the mechanisms for functional recovery in SCI rats after intravenous transplantation of MSCs derived from human umbilical cord blood. Sprague-Dawley rats were randomly assigned to receive either MSCs (1 × 10(6) cells/0.5 ml) or PBS into the tail vein immediately after SCI. They were then evaluated by the Basso-Beattie-Bresnahan (BBB) locomotor rating scale weekly for 8 weeks and by somatosensory evoked potentials (SSEPs) 8 weeks after transplantation. MSC-treated rats showed a modest but significant improvement in BBB scores and latencies of SSEPs, compared with PBS controls. When human-specific Alu element was measured in the spinal cord, it was detected only 1 h after transplantation, suggesting transient engraftment of MSCs. Inflammatory cytokines were also determined using RT-PCR or Western blot in spinal cord extracts. In MSC-treated rats, the level of proinflammatory cytokine IL-1β was decreased, but that of anti-inflammatory cytokine IL-10 was increased. MSCs also immediately suppressed IL-6 at 1 h posttransplantation. However, the response of IL-6, which has an immunoregulatory role, was increased 1-3 days after transplantation. In addition, we quantified microglia/macrophage stained with Iba-1 around the damaged spinal cord using immunohistochemistry. A proportion of activated microglia and macrophages in total Iba-1(+) cells was significantly decreased in MSC-treated rats, compared with PBS controls. These results suggest that early immunomodulation by intravenously transplanted MSCs is a potential underlying mechanism for functional recovery after SCI.
-
Exploring Erythropoietin and G-CSF Combination Therapy in Chronic Stroke Patients
International Journal of Molecular Sciences.
|
Pubmed ID: 27043535 Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) are known to have neuroprotective actions. Based on previous reports showing the synergistic effects of EPO+G-CSF combination therapy in experimental models, we investigated the safety of EPO+G-CSF combination therapy in patients with chronic stroke. In a pilot study, 3 patients were treated with EPO and G-CSF for 5 consecutive days, with follow-up on day 30. In an exploratory double-blind study, 6 patients were allocated to treatment with either EPO+G-CSF or placebo. Treatment was applied once a day for 5 days per month over 3 months. Participants were followed up for 6 months. To substantiate safety, vital signs, adverse events, and hematological values were measured on days 0, 5, and 30 in each cycle and on day 180. Functional outcomes were determined on day 0 and 180. In the laboratory measurements, EPO+G-CSF combination therapy significantly elevated erythropoietin, CD34⁺ hematopoietic stem cells, white blood cells, and neutrophils on day 5 of each cycle. There were no observations of serious adverse events. In the functional outcomes, the grip power of the dominant hand was increased in the EPO+G-CSF treatment group. In conclusion, this exploratory study suggests a novel strategy of EPO+G-CSF combination therapy for stroke patients.
-
Differential Expression of Extracellular Matrix and Adhesion Molecules in Fetal-Origin Amniotic Epithelial Cells of Preeclamptic Pregnancy
PloS One.
|
Pubmed ID: 27218821 Preeclampsia is a common disease that can occur during human pregnancy and is a leading cause of both maternal and neonatal morbidity and mortality. Inadequate trophoblast invasion and deficient remodeling of uterine spiral arteries are associated with preeclampsia (PE). The development of this syndrome is thought to be related to multiple factors. Recently, we isolated patient-specific human amniotic epithelial cells (AECs) from the placentas of 3 women with normal pregnancy and 3 with preeclamptic pregnancy. Since the characteristics of human AECs in PE are different from those in normal pregnancy, we sought to confirm the genes differentially expressed between preeclamptic pregnancy and normal pregnancy. Therefore, we performed transcriptome analysis to investigate the candidate genes associated with the possible pathophysiology of preeclampsia. Pathway analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) and Kyoto Encyclopedia of Genes and Genomes (KEGG) online resource. In this study, we selected a total of 12 pathways and focused on extracellular matrix-related and biological adhesion molecules. Using RT-PCR array and real-time PCR, we confirmed that COL16A1, ITGB2, and LAMA3 were significantly up-regulated, but ITGA1, ITGA3, ITGA6, MMP1, MMP3, MMP10 and MMP11 were significantly down-regulated in preeclamptic fetal origin cells. Taken together, we suggest that the genes and pathways identified here may be responsible for the occurrence and development of PE, and controlling their expression may play a role in communication with fetal-maternal placenta to keep normal pregnancy.
-
-
-
-
-
Astroglial Activation by an Enriched Environment After Transplantation of Mesenchymal Stem Cells Enhances Angiogenesis After Hypoxic-Ischemic Brain Injury
International Journal of Molecular Sciences.
|
Pubmed ID: 27649153 Transplantation of mesenchymal stem cells (MSCs) has paracrine effects; however, the effects are known to be largely limited. Here we investigated the combination effects of cell transplantation and enriched environment (EE) in a model of hypoxic-ischemic brain injury. Brain damage was induced in seven-day-old mice by unilateral carotid artery ligation and exposure to hypoxia (8% O₂ for 90 min). At six weeks of age, the mice were randomly assigned to four groups: phosphate-buffered saline (PBS)-control (CON), PBS-EE, MSC-CON, and MSC-EE. Rotarod and grip strength tests were performed to evaluate neurobehavioral functions. Histologic evaluations were also performed to confirm the extent of astrocyte activation and endogenous angiogenesis. An array-based multiplex ELISA and Western blot were used to identify growth factors in vivo and in vitro. Two weeks after treatment, levels of astrocyte density and angiogenic factors were increased in MSC-EE mice, but glial scarring was not increased. Eight weeks after treatment, angiogenesis was increased, and behavioral outcomes were synergistically improved in the MSC-EE group. Astrocytes co-cultured with MSCs expressed higher levels of angiogenic factors than astrocytes cultured alone. The mechanisms of this synergistic effect included enhanced repair processes, such as increased endogenous angiogenesis and upregulation of angiogenic factors released from activated astrocytes.
-
-
Elucidation of Relevant Neuroinflammation Mechanisms Using Gene Expression Profiling in Patients with Amyotrophic Lateral Sclerosis
PloS One.
|
Pubmed ID: 27812125 Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by damage of motor neurons. Recent reports indicate that inflammatory responses occurring within the central nervous system contribute to the pathogenesis of ALS. We aimed to investigate disease-specific gene expression associated with neuroinflammation by conducting transcriptome analysis on fibroblasts from three patients with sporadic ALS and three normal controls. Several pathways were found to be upregulated in patients with ALS, among which the toll-like receptor (TLR) and NOD-like receptor (NLR) signaling pathways are related to the immune response. Genes-toll-interacting protein (TOLLIP), mitogen-activated protein kinase 9 (MAPK9), interleukin-1β (IL-1β), interleukin-8 (IL-8), and chemokine (C-X-C motif) ligand 1 (CXCL1)-related to these two pathways were validated using western blotting. This study validated the genes that are associated with TLR and NLR signaling pathways from different types of patient-derived cells. Not only fibroblasts but also induced pluripotent stem cells (iPSCs) and neural rosettes from the same origins showed similar expression patterns. Furthermore, expression of TOLLIP, a regulator of TLR signaling pathway, decreased with cellular aging as judged by changes in its expression through multiple passages. TOLLIP expression was downregulated in ALS cells under conditions of inflammation induced by lipopolysaccharide. Our data suggest that the TLR and NLR signaling pathways are involved in pathological innate immunity and neuroinflammation associated with ALS and that TOLLIP, MAPK9, IL-1β, IL-8, and CXCL1 play a role in ALS-specific immune responses. Moreover, changes of TOLLIP expression might be associated with progression of ALS.
-
In Vivo Expression of Reprogramming Factors Increases Hippocampal Neurogenesis and Synaptic Plasticity in Chronic Hypoxic-Ischemic Brain Injury
Neural Plasticity.
|
Pubmed ID: 27900211 Neurogenesis and synaptic plasticity can be stimulated in vivo in the brain. In this study, we hypothesized that in vivo expression of reprogramming factors such as Klf4, Sox2, Oct4, and c-Myc would facilitate endogenous neurogenesis and functional recovery. CD-1® mice were induced at 1 week of age by unilaterally carotid artery ligation and exposure to hypoxia. At 6 weeks of age, mice were injected GFP only or both four reprogramming factors and GFP into lateral ventricle. Passive avoidance task and open field test were performed to evaluate neurobehavioral function. Neurogenesis and synaptic activity in the hippocampus were evaluated using immunohistochemistry, qRT-PCR, and/or western blot analyses. Whereas BrdU(+)GFAP(+) cells in the subgranular zone of the hippocampus were not significantly different, the numbers of BrdU(+)βIII-tubulin(+) and BrdU(+)NeuN(+) cells were significantly higher in treatment group than control group. Expressions of synaptophysin and PSD-95 were also higher in treatment group than control group. Importantly, passive avoidance task and open field test showed improvement in long-term memory and decreased anxiety in treatment group. In conclusion, in vivo expression of reprogramming factors improved behavioral functions in chronic hypoxic-ischemic brain injury. The mechanisms underlying these repair processes included endogenous neurogenesis and synaptic plasticity in the hippocampus.
-
-
-
Patients with Non-ambulatory Cerebral Palsy Have Higher Sclerostin Levels and Lower Bone Mineral Density Than Patients with Ambulatory Cerebral Palsy
Bone.
|
Pubmed ID: 28720522 Bone loss is a serious clinical issue in patients with cerebral palsy (CP). Sclerostin has garnered interest as a key mechanosensor in osteocytes, leading to considerations of the therapeutic utilization of anti-sclerostin medications. This study was undertaken to determine associations among mechanical unloading, sclerostin levels, and bone imbalance in patients with CP. A total of 28 patients with CP participated in this cross-sectional study. The following measurements were taken: anthropometrics, clinical diagnosis of CP subtype and ambulatory status, bone mineral density (BMD) z-scores at the lumbar spine and hip, and blood biochemical markers, including sclerostin, parathyroid hormone (PTH), osteocalcin, C-terminal telopeptide, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, creatinine, calcium, and phosphorus. In analysis according to CP subtype, patients with spastic CP showed significantly lower BMD z-scores at the lumbar spine and femur neck regions than patients with dyskinetic CP. In analysis according to ambulatory status, patients with non-ambulatory CP showed significantly lower BMD z-scores at all lumbar spine and femoral sites, lower PTH and creatinine levels, and higher plasma sclerostin levels than patients with ambulatory CP. In regression analysis, ambulatory status was a significant determinant of plasma sclerostin levels. This study is the first to report on sclerostin levels and BMD in patients with CP, based on the hypothesis that patients who lack sufficient weight-bearing activities would show increased sclerostin levels and decreased BMD scores, compared with patients who sustain relatively sufficient physical activity. Therefore, this report may provide clinical insights for clinicians considering ambulatory status, sclerostin levels, and bone loss in patients with CP.
-
Analysis of Structure-function Network Decoupling in the Brain Systems of Spastic Diplegic Cerebral Palsy
Human Brain Mapping.
|
Pubmed ID: 28731515 Manifestation of the functionalities from the structural brain network is becoming increasingly important to understand a brain disease. With the aim of investigating the differential structure-function couplings according to network systems, we investigated the structural and functional brain networks of patients with spastic diplegic cerebral palsy with periventricular leukomalacia compared to healthy controls. The structural and functional networks of the whole brain and motor system, constructed using deterministic and probabilistic tractography of diffusion tensor magnetic resonance images and Pearson and partial correlation analyses of resting-state functional magnetic resonance images, showed differential embedding of functional networks in the structural networks in patients. In the whole-brain network of patients, significantly reduced global network efficiency compared to healthy controls were found in the structural networks but not in the functional networks, resulting in reduced structural-functional coupling. On the contrary, the motor network of patients had a significantly lower functional network efficiency over the intact structural network and a lower structure-function coupling than the control group. This reduced coupling but reverse directionality in the whole-brain and motor networks of patients was prominent particularly between the probabilistic structural and partial correlation-based functional networks. Intact (or less deficient) functional network over impaired structural networks of the whole brain and highly impaired functional network topology over the intact structural motor network might subserve relatively preserved cognitions and impaired motor functions in cerebral palsy. This study suggests that the structure-function relationship, evaluated specifically using sparse functional connectivity, may reveal important clues to functional reorganization in cerebral palsy. Hum Brain Mapp 38:5292-5306, 2017. © 2017 Wiley Periodicals, Inc.
-
Outcomes of Intrathecal Baclofen Therapy in Patients with Cerebral Palsy and Acquired Brain Injury
Medicine.
|
Pubmed ID: 28834868 Intrathecal baclofen (ITB) has been known to reduce spasticity which did not respond to oral medications and botulinum toxin treatment. However, few results have been reported comparing the effects of ITB therapy in patients with cerebral palsy (CP) and acquired brain injury. This study aimed to investigate beneficial and adverse effects of ITB bolus injection and pump therapy in patients with CP and to compare outcomes to patients with acquired brain injury such as traumatic brain injury and hypoxic brain injury. ITB test trials were performed in 37 patients (19 CP and 18 acquired brain injury). Based on ambulatory function, CP patients were divided into 2 groups: 11 patients with nonambulatory CP and 8 patients with ambulatory CP. Change of spasticity was evaluated using the Modified Ashworth Scale. Additional positive or negative effects were also evaluated after ITB bolus injection. In patients who received ITB pump implantation, outcomes of spasticity, subjective satisfaction and adverse events were evaluated until 12 months post-treatment. After ITB bolus injection, 32 patients (86.5%) (CP 84.2% versus acquired brain injury 88.9%) showed a positive response of reducing spasticity. However, 8 patients with CP had negative adverse effects. Particularly, 3 ambulatory CP patients showed standing impairment and 1 ambulatory CP patient showed impaired gait pattern such as foot drop because of excessive reduction of lower extremity muscle tone. Ambulatory CP patients received ITB pump implantation less than patients with acquired brain injury after ITB test trials (P = .003 by a chi-squared test). After the pump implantation, spasticity was significantly reduced within 1 month and the effect maintained for 12 months. Seventeen patients or their caregivers (73.9%) were very satisfied, whereas 5 patients (21.7%) suffered from adverse events showed no subjective satisfaction. In conclusion, ITB therapy was effective in reducing spasticity in patients with CP and acquired brain injury. Before ITB pump implantation, it seems necessary to perform the ITB bolus injection to verify beneficial effects and adverse effects especially in ambulatory CP.
-
-
Elucidation of Gene Expression Patterns in the Brain After Spinal Cord Injury
Cell Transplantation.
|
Pubmed ID: 28933220 Spinal cord injury (SCI) is a devastating neurological disease. The pathophysiological mechanisms of SCI have been reported to be relevant to central nervous system injury such as brain injury. In this study, gene expression of the brain after SCI was elucidated using transcriptome analysis to characterize the temporal changes in global gene expression patterns in a SCI mouse model. Subjects were randomly classified into 3 groups: sham control, acute (3 h post-injury), and subacute (2 wk post-injury) groups. We sought to confirm the genes differentially expressed between post-injured groups and sham control group. Therefore, we performed transcriptome analysis to investigate the enriched pathways associated with pathophysiology of the brain after SCI using Database for Annotation Visualization, and Integrated Discovery (DAVID), which yielded Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Following enriched pathways were found in the brain: oxidative phosphorylation pathway; inflammatory response pathways-cytokine-cytokine receptor interaction and chemokine signaling pathway; and endoplasmic reticulum (ER) stress-related pathways-antigen processing and presentation and mitogen-activated protein kinase signaling pathway. Oxidative phosphorylation pathway was identified at acute phase, while inflammation response and ER stress-related pathways were identified at subacute phase. Since the following pathways-oxidative phosphorylation pathway, inflammatory response pathways, and ER stress-related pathways-have been well known in the SCI, we suggested a link between SCI and brain injury. These mechanisms provide valuable reference data for better understanding pathophysiological processes in the brain after SCI.
-
Age-Related Changes in Bimanual Instrument Playing with Rhythmic Cueing
Frontiers in Psychology.
|
Pubmed ID: 29085309 Deficits in bimanual coordination of older adults have been demonstrated to significantly limit their functioning in daily life. As a bimanual sensorimotor task, instrument playing has great potential for motor and cognitive training in advanced age. While the process of matching a person's repetitive movements to auditory rhythmic cueing during instrument playing was documented to involve motor and attentional control, investigation into whether the level of cognitive functioning influences the ability to rhythmically coordinate movement to an external beat in older populations is relatively limited. Therefore, the current study aimed to examine how timing accuracy during bimanual instrument playing with rhythmic cueing differed depending on the degree of participants' cognitive aging. Twenty one young adults, 20 healthy older adults, and 17 older adults with mild dementia participated in this study. Each participant tapped an electronic drum in time to the rhythmic cueing provided using both hands simultaneously and in alternation. During bimanual instrument playing with rhythmic cueing, mean and variability of synchronization errors were measured and compared across the groups and the tempo of cueing during each type of tapping task. Correlations of such timing parameters with cognitive measures were also analyzed. The results showed that the group factor resulted in significant differences in the synchronization errors-related parameters. During bimanual tapping tasks, cognitive decline resulted in differences in synchronization errors between younger adults and older adults with mild dimentia. Also, in terms of variability of synchronization errors, younger adults showed significant differences in maintaining timing performance from older adults with and without mild dementia, which may be attributed to decreased processing time for bimanual coordination due to aging. Significant correlations were observed between variability of synchronization errors and performance of cognitive tasks involving executive control and cognitive flexibility when asked for bimanual coordination in response to external timing cues at adjusted tempi. Also, significant correlations with cognitive measures were more prevalent in variability of synchronization errors during alternative tapping compared to simultaneous tapping. The current study supports that bimanual tapping may be predictive of cognitive processing of older adults. Also, tempo and type of movement required for instrument playing both involve cognitive and motor loads at different levels, and such variables could be important factors for determining the complexity of the task and the involved task requirements for interventions using instrument playing.
-
-
Get cutting-edge science videos from JoVE sent straight to your inbox every month.