Multilineage-differentiating stress-enduring (Muse) cells are newly established pluripotent stem cells. The aim of the present study was to examine the potential of the systemic administration of ...Muse cells as an effective treatment for subacute SCI. We intravenously administered the clinical product “CL2020” containing Muse cells to a rat model two weeks after mid-thoracic spinal cord contusion. Eight experimental animals received CL2020, and twelve received the vehicle. Behavioral analyses were conducted over 20 weeks. Histological evaluations were performed. After 20 weeks of observation, diphtheria toxin was administered to three CL2020-treated animals to selectively ablate human cell functions. Hindlimb motor functions significantly improved from 6 to 20 weeks after the administration of CL2020. The cystic cavity was smaller in the CL2020 group. Furthermore, larger numbers of descending 5-HT fibers were preserved in the distal spinal cord. Muse cells in CL2020 were considered to have differentiated into neuronal and neural cells in the injured spinal cord. Neuronal and neural cells were identified in the gray and white matter, respectively. Importantly, these effects were reversed by the selective ablation of human cells by diphtheria toxin. Intravenously administered Muse cells facilitated the therapeutic potential of CL2020 for severe subacute spinal cord injury.
BACKGROUND AND PURPOSE—Multilineage-differentiating stress-enduring cells are endogenous nontumorigenic reparative pluripotent-like stem cells found in bone marrow, peripheral blood, and connective ...tissues. Topically administered human multilineage-differentiating stress-enduring cells into rat/mouse stroke models differentiated into neural cells and promoted clinically relevant functional recovery. However, critical questions on the appropriate timing and dose, and safety of the less invasive intravenous administration of clinical-grade multilineage-differentiating stress-enduring cell–based product CL2020 remain unanswered.
METHODS—Using an immunodeficient mouse lacunar model, CL2020 was administered via the cervical vein in different doses (high dose=5×10 cells/body; medium dose=1×10 cells/body; low dose=5×10 cells/body) at subacute phase (≈9 days after onset) and chronic phase (≈30 days). Cylinder test, depletion of human cells by diphtheria toxin administration, immunohistochemistry, and human specific-genome detection were performed.
RESULTS—Tumorigenesis and adverse effects were not detected for up to 22 weeks. The high-dose group displayed significant functional recovery compared with the vehicle group in cylinder test in subacute-phase–treated and chronic-phase–treated animals after 6 weeks and 8 weeks post-injection, respectively. In the high-dose group of subacute-phase–treated animals, robust and stable recovery in cylinder test persisted up to 22 weeks compared with the vehicle group. In both groups, intraperitoneal injection of diphtheria toxin abrogated the functional recovery. Anti-human mitochondria revealed CL2020 distributed mainly in the peri-infarct area at 1, 10, and 22 weeks and expressed NeuN (neuronal nuclei)- and MAP-2 (microtubule-associated protein-2)-immunoreactivity.
CONCLUSIONS—Intravenously administered CL2020 was safe, migrated to the peri-infarct area, and afforded functional recovery in experimental stroke.
Radiation therapy is sometimes performed to control intracranial acute lymphoblastic leukemia (ALL), but may lead to radiation-induced malignant glioma. The clinical, radiological, histological, and ...molecular findings are described of three cases of radiation-induced glioblastoma after the treatment for ALL. They received radiation therapy at age 6–8 years. The latency from radiation therapy to the onset of radiation-induced glioblastoma was 5–10 years. Magnetic resonance imaging demonstrated diffuse lesions with multiple small enhanced lesions in all cases. Histological examination showed that the tumors consisted of mainly small round astrocytic atypical cells in one case, and astrocytic atypical cells with elongated cytoplasm and nuclear pleomorphism with small cell component in two cases. Microvascular proliferation was present in all cases. Immunohistochemical analysis for B-Raf V600E, and mutational analysis for the isocitrate dehydrogenase (IDH) 1, IDH2, and H3F3A gene revealed the wild-type alleles in all three cases. The integrated diagnoses were IDH wild-type glioblastoma, and local irradiation and concomitant temozolomide were performed. After the initial treatment, significant shrinkage of the diffuse lesion and enhanced lesion was found in all cases. Radiation-induced glioblastoma occurring after the treatment for ALL had unique clinical, radiological, histological, and molecular characteristics in our three cases.
INTRODUCTION Multilineage-differentiating stress-enduring (Muse) cells are pluripotent stem cells, which can be harvested from the bone marrow. After transplantation, Muse cells can migrate to an ...injured site of the body and exert repair effects. METHODS We used a rat model of thoracic spinal cord contusion injury. For Muse cells transplantation, clinical product "CL2020" containing 300,000 Muse cells were administered intravenously one day after the mid-thoracic injury. Animals were divided into CL2020 (n = 11) and the vehicle treated (n = 15) groups. Behavioral and histological evaluations were conducted over 8 weeks to see whether intravenous CL2020 administration provide therapeutic effects for spinal cord injury. RESULTS Hindlimb motor function significantly improved after CL2020 transplantations. Importantly, the effects were reverted by the human-selective diphtheria toxin. In immunohistochemical analyses, cystic cavity formed after the injury was smaller in CL2020 group. Furthermore, more numbers of descending 5-HT fibers were preserved distal to the injury site after CL2020 administration. Eight weeks after the injury, Muse cells in CL2020 were confirmed to differentiate most predominantly into neuronal cells in the injured spinal cord. CONCLUSION Acutely after SCI, Muse cells in CL2020 can reach to the injured spinal cord after intravenous administration and differentiate into neuronal cells. Muse cells in CL2020 facilitated nerve fibers preservation, and exert therapeutic potential for severe SCI.
Multilineage-differentiating stress-enduring (Muse) cells are pluripotent stem cells, which can be harvested from the bone marrow. After transplantation, Muse cells can migrate to an injured site of ...the body and exert repair effects. However, it remains unknown whether Muse cell transplantation can be an effective treatment in spinal cord injury (SCI).
The authors used a rat model of thoracic spinal cord contusion injury. For Muse cell transplantation, the clinical product CL2020 containing 300,000 Muse cells was administered intravenously 1 day after midthoracic SCI. Animals were divided into CL2020 (n = 11) and vehicle-treated (n = 15) groups. Behavioral and histological evaluations were conducted over a period of 8 weeks to see whether intravenous CL2020 administration provided therapeutic effects for SCI. The effects of human-selective diphtheria toxin on reversion of the therapeutic effects of CL2020 were also investigated.
Hindlimb motor function significantly improved after CL2020 transplantations. Importantly, the effects were reverted by the human-selective diphtheria toxin. In immunohistochemical analyses, the cystic cavity formed after the injury was smaller in the CL2020 group. Furthermore, higher numbers of descending 5-hydroxytryptamine (5-HT) fibers were preserved distal to the injury site after CL2020 administration. Eight weeks after the injury, Muse cells in CL2020 were confirmed to differentiate most predominantly into neuronal cells in the injured spinal cord.
Following SCI, Muse cells in CL2020 can reach the injured spinal cord after intravenous administration and differentiate into neuronal cells. Muse cells in CL2020 facilitated nerve fiber preservation and exerted therapeutic potential for severe SCI.
Spinal dural arteriovenous fistula (DAVF) occurs at any spinal level, but the clinical characteristics of lumbosacral DAVF have not been well documented. The purpose of this study was to evaluate ...clinical characteristics of lumbosacral DAVF and compare these features with those in thoracic DAVF.
Twenty-five consecutive patients with 16 thoracic and 9 lumbosacral DAVFs were included (mean age, 63.9 years; 20 men). All patients presented with progressive myelopathy. Preoperative and postoperative neurologic deficits were compared between thoracic and lumbosacral DAVF groups. Using magnetic resonance imaging, the extent of T2 high-intensity areas and signal flow voids were documented. Follow-up after surgical interventions ranged from 6 to 96 months (mean, 38.1 months).
Preoperatively, patients suffering lumbosacral DAVF tended to be more severely disabled compared with thoracic DAVF patients. Lumbosacral DAVF patients exhibited diminished patellar (P = 0.04) and Achilles tendon reflexes (P < 0.01), while most thoracic DAVF patients exhibited hyperreflexia. In magnetic resonance imaging, signal flow voids around the spinal cord were evident in only 4 of 9 lumbosacral DAVF patients (P = 0.012). Rather, a serpentine signal flow void of the filum terminale was a hallmark of lumbosacral DAVFs to distinguish them from thoracic DAVFs. In the lumbosacral DAVF group, postoperative improvements were significantly better in micturition function (P = 0.02).
In lumbosacral DAVF, postoperative micturition function recovery was superior to thoracic DAVF. Intradural lumbar signal flow void is indicative of lumbosacral DAVF. For appropriate management, it is important to recognize these differences between lumbosacral and thoracic DAVF.
The sudden onset of oculomotor nerve (OCN) paralysis is a symptom that suggests the impending rupture of a cerebral aneurysm. The mechanism of such OCN paralysis has been proposed as direct ...compression by an enlarged aneurysm and/or blood leakage from an aneurysm. In this article, we report a rare case of aneurysm enlargement in the posterior communicating (Pcom) artery direction to compress the OCN. A 60-year-old woman presented with left OCN paralysis with both ptosis and mydriasis. Although CT did not show any intracranial hemorrhage, CT angiography revealed a left internal carotid- Pcom (IC-PC) aneurysm. We diagnosed it as an impending rupture of the aneurysm that required emergency surgery. Intraoperative findings revealed that the fetal Pcom artery, but not the aneurysm, compressed the OCN. We performed neck clipping and partial wrapping of the aneurysm to change the Pcom artery direction to decompress the OCN. Her symptoms improved after surgery. There was a case report in which the Pcom artery compressed the OCN directly instead of the aneurysm, suggesting that it was caused by an abnormal running of the fetal Pcom artery. In this case, aneurysm clipping reduces the volume of the aneurysm to normalize the Pcom artery direction, resulting in neurovascular decompression of the oculomotor nerve.
Introduction: The one-year mortality associations in hemodialysis (HD) patients who underwent surgical intervention after traumatic brain injury (TBI) has been reported as approximately 75% in ...population-based nationwide study in Taiwan, although it has not been well investigated in Japan.Materials and Methods: In this study, the demographic characteristics of consecutive 59 HD patients (M:F=36:23, 75±12 y.o.) with acute traumatic intracranial hematoma (t-ICH) were collected and analyzed to compare to those in 293 non-HD controls (M:F=174:119, 73±13 y.o.). In all HD patients, chronic HD was suspended temporarily for at least 24 hours after trauma, and then resumed intermittently for 3 times a week, using Nafamostat mesilate under slow filtration as blood flow at 150 mL/h. The type of t-ICH, Glasgow Coma Scale (GCS) score on admission, and Glasgow Outcome Scale (GOS) score on discharge were compared between 2 groups.Results: Configuration of the main type of t-ICH, as well as GCS score on admission, was not different between 2 groups. GOS score was significantly worse in HD than non-HD group. In surgically treated HD patients, the mortality seemed markedly lower than those in Taiwan.Conclusion: The clinical outcome of HD patients who underwent surgical intervention after TBI may be more favorable in Japan compared to those in Taiwan. Such difference of outcome may be affected by the difference in configuration of patients and/or medico-social factors between countries.
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