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Shi X.,Peking University | Kang Y.,Beijing Hongtianji Neuroscience Academy | Kang Y.,Beijing Rehabilitation Center | Hu Q.,Peking University | And 9 more authors.
Brain Research | Year: 2010

Trials of neuroprotection in ischemic stroke mainly concern gray matter protection, with little information on white matter damage. Olfactory ensheathing cells (OECs) are capable of providing continuous neurotrophic factor and of promoting growth and remyelination of damaged axons. We evaluated OECs for the repair of white matter after transplantation in middle cerebral artery occlusion (MCAO) rat. OECs were cultured from the olfactory bulbs of adult green fluorescent protein (GFP)-expressing transgenic rats and transplanted into peri-infarct basal ganglia imminently after reperfusion. The mortality, neurological score, and function were record everyday until 56 days. At 24 h and 56 days, the infarction volume, the Luxol-fast blue (LFB) staining, and Neurofilament (NF) immunohistochemistry and Western blot were performed to assess the demyelination and remyelination in white matter. OECs transplantation reduced the infarct volume, decreased mortality, and improved neurological deficits in 56 days after MCAO. LFB marked myelin, NF-positive immunohistochemistry, and Western blot indicated that the remyelination and axon regeneration in OEC transplanted rat were significant. In conclusion, OECs can protect the white matter from ischemic injury, but the potential mechanisms of transplanted OEC-mediated recovery need further studies to identify. © 2009 Elsevier B.V. All rights reserved.


Li Y.,Beijing Hongtianji Neuroscience Academy | Li Y.,Taishan Medical University | Bao J.,Beijing Hongtianji Neuroscience Academy | Bao J.,First Affiliated Hospital of Xin Jiang Medical University Urumqi | And 10 more authors.
Anatomical Record | Year: 2011

Amyotrophic lateral sclerosis (ALS) is a progressively fatal, incurable, neurodegenerative disorder. In this study, we investigated whether olfactory ensheathing cells (OEC) transplantation could provide protection to motor neurons and enable remyelination in mutant SOD1G93A transgenic rats with ALS. Seventy-two rats were divided into four groups: SOD1G93A rats (n = 20); medium+SOD1G93A rats (n = 20); OECs+SOD1G93A rats (n = 24); and another eight wild-type rats were used as controls. About 5 μL (1 × 105) OECs in DF12 medium was injected into the dorsal funiculus of the thoracic spinal cord at a predetermined depth. Survival analysis revealed a significant increase in the survival time in OEC+SOD1G93A rats. Body weight records and inclined board test showed a significant difference between OEC+SOD1G93A and SOD1G93A from the onset at 7 days to 11 days (P < 0.05). Four weeks following transplantation, motor neuron counts in the ventral horn of the spinal cord noted a significant motor neuron loss in SOD1G93A rats when compared with wild-type rats (P < 0.001), and much less neuronal loss and collapse was noted in OEC+SOD1G93A rats when compared with SOD1G93A rats(P < 0.001); immunohistochemistry and Western blot analysis of choline acetyltransferase supported the motor neuron count. Images of confocal microscope indicated that the transplanted OECs had survived for more than 4 weeks and migrated 4.2 mm through the spinal cord. Evidence of remyelination of transplanted OEC was captured with triple fluorescence labeling of green fluorescent protein, neurofilament, and myelin basic protein and was further confirmed by Western blot analysis of MPB. In conclusion, the transplanted OECs could serve as a source of neuroprotection and remyelination to modify the ALS microenvironment. © 2011 Wiley-Liss, Inc.


Chen L.,Center for Neurorestoratology | Chen L.,Beijing Hongtianji Neuroscience Academy | Chen D.,Beijing Hongtianji Neuroscience Academy | Xi H.,Center for Neurorestoratology | And 14 more authors.
Cell Transplantation | Year: 2012

Our previous series of studies have proven that olfactory ensheathing cell (OEC) transplantation appears to be able to slow the rate of clinical progression after OEC transplantation in the first 4 months and cell intracranial (key points for neural network restoration, KPNNR) and/or intraspinal (impaired segments) implants provide benefit for patients (including both the bulbar onset and limb onset subtypes) with amyotrophic lateral sclerosis (ALS). Here we report the results of cell therapy in patients with ALS on the basis of long-term observation following multiple transplants. From March of 2003 to January of 2010, 507 ALS patients received our cellular treatment. Among them, 42 patients underwent further OEC therapy by the route of KPNNR for two or more times (two times in 35 patients, three times in 5 patients, four times in 1 patient, and five times in 1 patient). The time intervals are 13.1 (6-60) months between the first therapy and the second one, 15.2 (8-24) months between the second therapy and the third one, 16 (6-26) months between the third therapy and the fourth one, and 9 months between the fourth therapy and the fifth time. All of the patients exhibited partial neurological functional recovery after each cell-based administration. Firstly, the scores of the ALS Functional Rating Scale (ALS-FRS) and ALS Norris Scale increased by 2.6 + 2.4 (0-8) and 4.9 + 5.2 (0-20) after the first treatment, 1.1 + 1.3 (0-5) and 2.3 + 2.9 (0-13) after the second treatment, 1.1 + 1.5 (0-4), and 3.4 + 6.9 (0-19) after the third treatment, 0.0 + 0.0 (0-0), and 2.5 + 3.5 (0-5) after the fourth treatment, and 1 point after the fifth cellular therapy, which were evaluated by independent neurologists. Secondly, the majority of patients have achieved improvement in electromyogram (EMG) assessments after the first, second, third, and fourth cell transplantation. After the first treatment, among the 42 patients, 36 (85.7%) patients' EMG test results improved, the remaining 6 (14.3%) patients' EMG results showed no remarkable change. After the second treatment, of the 42 patients, 30 (71.4%) patients' EMG results improved, 11 (26.2%) patients showed no remarkable change, and 1 (2.4%) patient became worse. After the third treatment, out of the 7 patients, 4 (57.1%) patients improved, while the remaining 3 (42.9%) patients showed no change. Thirdly, the patients have partially recovered their breathing ability as demonstrated by pulmonary functional tests. After the first treatment, 20 (47.6%) patients' pulmonary function ameliorated. After the second treatment, 18 (42.9%) patients' pulmonary function improved. After the third treatment, 2 (28.6%) patients recovered some pulmonary function. After the fourth and fifth treatment, patients' pulmonary function did not reveal significant change. The results show that multiple doses of cellular therapy definitely serve as a positive role in the treatment of ALS. This repeated and periodic cellbased therapy is strongly recommended for the patients, for better controlling this progressive deterioration disorder. © 2012 Cognizant Comm. Corp.


Huang H.,Center for Neurorestoratology | Huang H.,Beijing Hongtianji Neuroscience Academy | Huang H.,Tsinghua University | Xi H.,Beijing Hongtianji Neuroscience Academy | And 6 more authors.
Cell Transplantation | Year: 2012

The neurorestorative effect of the parenchymal transplantation of olfactory ensheathing cells (OECs) for cord trauma remains clinically controversial. The aim of this article is to study the long-term result of OECs for patients with complete chronic spinal cord injury (SCI). One hundred and eight patients suffered from complete chronic SCI were followed up successfully within the period of 3.47 ± 1.12 years after OEC therapy. They were divided into two groups based on the quality and quantity of their rehabilitative training: group A (n = 79) in sufficient rehabilitation (or active movement-target enhancement-neurorehabilitation therapy, AMTENT) and group B (n = 29) in insufficient rehabilitation. All patients were assessed by using the American Spinal Injury Association (ASIA) standard and the International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS). Thirty-one patients were evaluated by the tests of magnetic resonance imaging (MRI), electromyography (EMG), and paravertebral sensory evoked potential (PVSEP). We found the following. 1) According to ASIA and IANR-SCIFRS assessment for all 108 patients, averaged motor scores increased from 37.79 ± 18.45 to 41.25 ± 18.18 (p < 0.01), light touch scores from 50.32 ± 24.71 to 55.90 ± 24.46 (p < 0.01), pin prick scores from 50.53 ± 24.92 to 54.53 ± 24.62 (p < 0.01); IANR-SCIFRS scores increased from 19.32 ± 9.98 to 23.12 ± 10.30 (p < 0.01). 2) The score changes in terms of motor, light touch, pin prick, and IANR-SCIFRS in group A were remarkably different (all p < 0.01). The score changes in group B were remarkably different in terms of motor (p < 0.05) and IANR-SCIFRS (p < 0.01), but not light touch or pin prick (p > 0.05). 3) Comparing group A with group B, the increased scores in terms of motor, light touch, and pin prick were remarkably different (all p < 0.01), but not IANR-SCIFRS (p > 0.05). 4) Fourteen of 108 patients (12.96%) became ASIA B from ASIA A; 18 of 108 (16.67%) became ASIA C from ASIA A. Nine of them (8.33%) improved their walk ability or made them rewalk by using a walker with or without assistance; 12 of 84 men (14.29%) improved their sex function. 5) MRI examinations were taken for 31 patients; there were no neoplasm, bleeding, swelling, cysts, neural tissue destruction or infection (abscess) or any other pathological changes in or around OEC transplant sites. 6) EMG examinations were done on 31 patients; 29 showed improvement and the remaining 2 had no change. PVSEP tests were performed in 31 patients; 28 showed improvements and the remaining 3 had no change. 7) No deterioration or complications were observed in our patients within the follow-up period. Our data suggest OEC therapy is safe and can improve neurological functions for patients with complete chronic SCI and ameliorate their quality of life; the AMTENT most likely plays a critical role in enhancing functional recovery after cell-based neurorestorotherapy. © 2012 Cognizant Comm. Corp.


Leng Z.,Xi'an Jiaotong University | Guo L.,Xi'an Jiaotong University | Sharma H.S.,Uppsala University | Huang H.,Beijing Hongtianji Neuroscience Academy | He X.,Xi'an Jiaotong University
CNS and Neurological Disorders - Drug Targets | Year: 2012

The International Association of Neurorestoratology (IANR) V and the 9th Global College of Neuroprotection and Neuroregeneration (GCNN) Conference with the 4th International Spinal Cord Injury Treatments & Trials (ISCITT) Symposium were successfully hosted in Xi'an, China on May 4th to 7th, 2012 by IANR, GCNN and the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University. More than 600 experts in the Neurorestoratology field from over 40 countries and regions attended this combined novel international summit. The purpose of the 4-day conference was to provide a platform for basic scientists and clinicians to share their latest discoveries and foster possible cooperation in the global Neurorestoratology field. The chairman of the Chinese Medical Doctor Association (CMDA) and former National Deputy Minister of Health, Dakui Yin inaugurated the joint conference in a gala opening ceremony and warmly welcomed the delegates.


Chen L.,Beijing Hongtianji Neuroscience Academy | Chen L.,Tsinghua University | Chen L.,Capital Medical University | Huang H.,Beijing Hongtianji Neuroscience Academy | And 4 more authors.
Cell Transplantation | Year: 2013

Cell transplantation is a potentially powerful approach for the alleviation of chronic pain. The strategy of cell transplantation for the treatment of pain is focused on cell-based analgesia and neural repair. (1) Adrenal medullary chromaffin cells and the PC12 cell line have been used to treat cancer pain and neuropathic pain in both animal models and human cases. As biological or living minipumps, these cells produce and secrete pain-reducing neuroactive substances if administered directly into the spinal subarachnoid space. (2) Cell implantation for pain neurorestorative therapy is a new concept and an emerging research field for pain control along with neural repair. Possible neurorestorative mechanisms include neuroprotective, neurotrophic, neuroreparative, neuroregenerative, neuromodulation, or neuroconstructive interventions, as well as immunomodulation and enhancing the microcirculation. These factors may ultimately restore the damaged or irritated condition of the lesioned nerves. The growing preclinical and clinical data show that neural stem/progenitor cells, olfactory ensheathing cells, mesenchymal stromal cells, and CD34+ cells have the capacity to manage intractable pain and improve neurological functions. Cell delivery routes include local, intrathecal, or intravascular implants. Although these strategies are still in their infancy phase for pain neurorestoratology, cell-based therapies could open up new avenues for the relief of pain. In this review, these aspects are critically analyzed based on our own investigations. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation. © 2013 Cognizant Comm. Corp.


Sun T.,The Beijing Army General Hospital | Ye C.,The Beijing Army General Hospital | Zhang Z.,The Beijing Army General Hospital | Wu J.,The Beijing Army General Hospital | Huang H.,Beijing Hongtianji Neuroscience Academy
Cell Transplantation | Year: 2013

The present study investigated the ability of cotransplantation of Schwann cells (SCs) and olfactory ensheathing cells (OECs) combined with treadmill training in facilitating neuronal plasticity and promoting hindlimb function recovery of subacute moderate thoracic (T10) spinal cord contusion in rats. Two weeks postinjury, SCs were injected directly into the lesion, while OECs were injected into the adjacent tissues. The treadmill training with the rats began postinjury on day 7, with each session lasting 20 ± 10 min per day, 5 days per week, for 10 weeks. At the 11th week postinjury, OECs were found migrating longitudinally and laterally from the injection site to the injury site through the gray and white matter, while some traveled along the central canal or pia. The SCs remained densely packed and concentrated at the transplant site. The transplanted SCs supported ingrowth of numerous, densely populated neurofilament-positive (NF+), MBP+ axons. The OECs promoted elongation of moderate NF+, GAP-43+ axons and a few MBP+ axons in parallel with OEC processes. The GFAP immunoreactivity in the spared tissue surrounding the graft of SCs and OECs at the lesion site was less intense than that in the DMEM group. Treadmill training had no effect on GFAP immunoreactivity. Treadmill training increased the number of TH-immunoreactive neurons in the gray matter of L2 spinal cord. Moreover, cotransplantation of OECs and SCs significantly increased the BBB score during 5-8 weeks postinjury alongside treadmill training between 5 and 11 weeks. Cotransplantation of OECs and SCs combined with treadmill training resulted in the highest BBB score at 4 and 11 weeks. The study details the differential mechanisms of neuronal plasticity: (1) axon growth and remyelination induced by cotransplantation of OECs and SCs and (2) neuron plasticity below the lesion enhanced by treadmill training. The synergistic effects of the combined strategy enhance functional recovery. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation. © 2013 Cognizant Comm. Corp.


Chen L.,Capital Medical University | Chen L.,Beijing Hongtianji Neuroscience Academy | Chen L.,Tsinghua University | Xi H.,Beijing Hongtianji Neuroscience Academy | And 10 more authors.
Cell Transplantation | Year: 2013

Stroke is the third leading cause of death worldwide and a huge perpetrator in adult disability. This pilot clinical study investigates the possible benefits of transplanting multiple cells in chronic stroke. A total of 10 consecutive stroke patients were treated by combination cell transplantation on the basis of an intraparenchymal approach from November 2003 to April 2011. There were six males and four females. Their age ranged from 42 to 87 years, and the course of disease varied from 6 months to 20 years. Six patients suffered cerebral infarction, and four patients suffered a brain hemorrhage. The olfactory ensheathing cells, neural progenitor cells, umbilical cord mesenchymal cells, and Schwann cells were injected through selected routes including intracranial parenchymal implantation, intrathecal implantation, and intravenous administration, respectively. The clinical neurological function was assessed carefully and independently before treatment and during a long-term follow-up using the Clinic Neurologic Impairment Scale and the Barthel index. All patients were followed up successfully from 6 months to 2 years after cell transplantation. Every subject achieved neurological function amelioration including improved speech, muscle strength, muscular tension, balance, pain, and breathing; most patients had an increased Barthel index score and Clinic Neurologic Impairment Scale score. These preliminary results demonstrate the novel strategy of combined multiple cell therapy based on intraparenchymal delivery: it appears to be relatively clinically safe and at least initially beneficial for chronic stroke patients. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation. © 2013 Cognizant Comm. Corp.


PubMed | Beijing Hongtianji Neuroscience Academy
Type: Journal Article | Journal: Anatomical record (Hoboken, N.J. : 2007) | Year: 2011

Amyotrophic lateral sclerosis (ALS) is a progressively fatal, incurable, neurodegenerative disorder. In this study, we investigated whether olfactory ensheathing cells (OEC) transplantation could provide protection to motor neurons and enable remyelination in mutant SOD1(G93A) transgenic rats with ALS. Seventy-two rats were divided into four groups: SOD1(G93A) rats (n = 20); medium+SOD1(G93A) rats (n = 20); OECs+SOD1(G93A) rats (n = 24); and another eight wild-type rats were used as controls. About 5 L (1 10(5)) OECs in DF12 medium was injected into the dorsal funiculus of the thoracic spinal cord at a predetermined depth. Survival analysis revealed a significant increase in the survival time in OEC+SOD1(G93A) rats. Body weight records and inclined board test showed a significant difference between OEC+SOD1(G93A) and SOD1(G93A) from the onset at 7 days to 11 days (P < 0.05). Four weeks following transplantation, motor neuron counts in the ventral horn of the spinal cord noted a significant motor neuron loss in SOD1(G93A) rats when compared with wild-type rats (P < 0.001), and much less neuronal loss and collapse was noted in OEC+SOD1(G93A) rats when compared with SOD1(G93A) rats(P < 0.001); immunohistochemistry and Western blot analysis of choline acetyltransferase supported the motor neuron count. Images of confocal microscope indicated that the transplanted OECs had survived for more than 4 weeks and migrated 4.2 mm through the spinal cord. Evidence of remyelination of transplanted OEC was captured with triple fluorescence labeling of green fluorescent protein, neurofilament, and myelin basic protein and was further confirmed by Western blot analysis of MPB. In conclusion, the transplanted OECs could serve as a source of neuroprotection and remyelination to modify the ALS microenvironment.


PubMed | Beijing Hongtianji Neuroscience Academy
Type: Journal Article | Journal: Anatomical record (Hoboken, N.J. : 2007) | Year: 2010

Clinical studies have expanded the therapeutic olfactory ensheathing cells (OECs) transplantation to different human Central Nervous System (CNS) diseases. In fact, the OEC transplantation in clinic is a mixture of olfactory bulb cells; they even have not demonstrated that they have such a subpopulation yet. However, as a source of OECs transplantation, the development and identification of human fetal OECs are still need more understanding, because some surgery try to restoration CNS injury with a more purity of OEC cultures generated by a number of different procedures. In this article, twelve human fetal olfactory bulb (OB) samples were obtained from six fetuses in 20 weeks of gestation, it was studied by immunofluorescence on histological sections and cultured cells with multiple antibodies under confocal microscopy. The P75NTR positive OB-OECs (olfactory ensheathing cell from the olfactory bulb) were present in both outer olfactory nerve layers and glomerular layer. The percentage of OB cells in culture, about 22.31 was P75NTR positive, 45.77 was S100beta, and 31.92 was GFAP. P75NTR and GFAP were coexpressed with S100beta, respectively; however, P75NTR was not coexpressed with GFAP in human fetal OECs. It is suggested that the localization and development of human OECs in OB are different to those in rodent, and the P75NTR immunohistological staining is still necessary to identify and characterize human fetal OECs in culture before transplantation.

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