Hongyun Huang

Fetal olfactory ensheathing cells transplantation in amyotrophic lateral sclerosis patients: a controlled pilot study

Abstract:u2002 This study was designed to clarify whether transplantation of fetal olfactory ensheathing cells (OECs) would affect the clinical course of patients with amyotrophic lateral sclerosis (ALS). Thirty‐five patients with probable or definite ALS were enrolled from December 2004 to September 2006; 15 patients received OECs transplantation and 20 patients did not receive OECs transplantation. OECs were cultured and injected into the bilateral corona radiata involving the pyramidal tracts of the frontal lobes. The primary end point used to indicate effectiveness was the rate of change according to the ALS Functional Rating Scale (ALS‐FRS) total score. All patients were tested five times at baseline and monthly intervals during a four‐month follow‐up period using assessment of ALS‐FRS. Thirty‐one patients (14 in the OECs treated group and 17 in the controls) completed the four‐month study; the remaining four patients were lost to follow‐up. Patients’ data were analyzed fouru2003months after OECs transplantation and at the end of the controlled period. There was no significant difference in the rate of progression as measured by the ALS‐FRS total score during the first twou2003months (pu2003>u20030.05). The functional deterioration, however, was significantly slower in the treated group than in the control group during the last twou2003months (pu2003<u20030.05). The mean (±SD) change for the ALS‐FRS total score was 0.07u2003±u20034.18 for the treated group and 6.12u2003±u20035.49 for the control group (pu2003=u20030.002) during the fouru2003months. Of the 14 patients in the treatment group, seven experienced neurological functional improvements, two were stable compared with their clinical status at entry, and the ALS‐FRS scores in the other five decreased by a mean of 4.4. Of the 17 patients in the control group, only one patient’s condition remained stable while the ALS‐FRS scores in the other 16 decreased by a mean of 6.5. The result indicates OECs transplantation appears to be able to slow the rate of clinical progression of ALS in the first fouru2003months posttransplantation.

Intracerebral transplantation of adipose-derived mesenchymal stem cells alternatively activates microglia and ameliorates neuropathological deficits in Alzheimer's disease mice.

Recent studies suggest that transplantation of mesenchymal stem cells might have therapeutic effects in preventing pathogenesis of several neurodegenerative disorders. Adipose-derived mesenchymal stem cells (ADSCs) are a promising new cell source for regenerative therapy. However, whether transplantation of ADSCs could actually ameliorate the neuropathological deficits in Alzheimers disease (AD) and the mechanisms involved has not yet been established. Here, we evaluated the therapeutic effects of intracerebral ADSC transplantation on AD pathology and spatial learning/memory of APP/PS1 double transgenic AD model mice. Results showed that ADSC transplantation dramatically reduced β-amyloid (Aβ) peptide deposition and significantly restored the learning/memory function in APP/PS1 transgenic mice. It was observed that in both regions of the hippocampus and the cortex there were more activated microglia, which preferentially surrounded and infiltrated into plaques after ADSC transplantation. The activated microglia exhibited an alternatively activated phenotype, as indicated by their decreased expression levels of proinflammatory factors and elevated expression levels of alternative activation markers, as well as Aβ-degrading enzymes. In conclusion, ADSC transplantation could modulate microglial activation in AD mice, mitigate AD symptoms, and alleviate cognitive decline, all of which suggest ADSC transplantation as a promising choice for AD therapy. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

Long-Term Outcome of Olfactory Ensheathing Cell Therapy for Patients with Complete Chronic Spinal Cord Injury:

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.

Olfactory ensheathing cell neurorestorotherapy for amyotrophic lateral sclerosis patients: benefits from multiple transplantations.

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 cell-based therapy is strongly recommended for the patients, for better controlling this progressive deterioration disorder.

Olfactory Ensheathing Cell Transplantation Into Spinal Cord Prolongs the Survival of Mutant SOD1G93A ALS Rats Through Neuroprotection and Remyelination

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. Anat Rec, 2011.

The immunohistochemical characterization of human fetal olfactory bulb and olfactory ensheathing cells in culture as a source for clinical CNS restoration.

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 S100β, and 31.92 was GFAP. P75NTR and GFAP were coexpressed with S100β, 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. Anat Rec, 2010.

Intracranial Transplant of Olfactory Ensheathing Cells Can Protect Both Upper and Lower Motor Neurons in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal disease that involves the degeneration of cortical and spinal motor neurons. Mutant SOD1G93A rats constitute a good animal model for this pathological condition. We have previously demonstrated that transplantation of neonatal olfactory ensheathing cells (OECs) into the dorsal funiculus of the spinal cord of mutant SOD1G93A transgenic rats increases the survival of spinal motor neurons and remyelinates the impaired axons through the pyramidal tract. In the present study, we examine whether intracranial cell implantation could also exert a similar effect on cortical motor neurons and on the lower motor neurons in the spinal cord. We injected OECs from the bulb of 7-day-old GFP green rats into the corona radiata of adult SOD1 mutant rats stereotaxically to observe any changes of the upper motor neurons as well as the lower motor neurons. We found that more motor neurons at both the motor cortices and ventral horns of the spinal cord survived in grafted ALS rats than in control rats. Prolonged survival and behavioral tests including a screen test, hind limb extension, rotarod, and gait control showed that the treated animals were better than the control group. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

Neurorestoratology : one of the most promising new disciplines at the forefront of neuroscience and medicine

Neurorestoratology is a new and emerging distinct discipline put forward on the basis of nervous restorable (neurorestorable) theory, which states that nerve damage to the central nervous system (CNS) can be restored. Neurorestorable theory in CNS was proposed by Huang et al based on clinical achievements obtained from cell-based neurorestorative therapy1. Neurorestoratology, same as neurology, neurosurgery, neurorehabilitation, etc is a distinct discipline in neuroscience and medicine. The Beijing Declaration of International Association of Neurorestoratology (IANR) determined its definition in 2009.2 The aim of neurorestoratology is to restore or promote recovery of damaged or lost neuronal functions. As depicted in Figure 1,3 it can clearly be seen that there was a blank space – indicated by the question mark in the figure – that needed to be filled with a new discipline, neurorestoratology, so it can be likened to an inexorable biological law and its development to a natural process quite similar to that of the periodic law of chemistry discovered and proposed by Dmitri Mendeleev. In recent years, neurorestoratology has become one of the most interesting core areas of neuroscience and medicine worldwide, representing a novel aspect of translational medicine.

Beijing Declaration of International Association of Neurorestoratology

1. With rapid development of basic and clinical advancement on neural restoration, neurorestoratology has become a distinct discipline within neurosciences. 2. World wide neurological impairment due to neurodegeneration and neural injury is a major factor reducing human longevity and quality of life. Neurorestoratology seeks therapeutic solutions to this problem. 3. Neurorestoratology is the sub-discipline of neuroscience that studies neural regeneration, repair and replacement of damaged components of the nervous system, neuroplasticity, neuroprotection and neuromodulatory mechanisms of recovery. The goal of neurorestoratology is to promote recovery of neural function. 4. The research and scope of neurorestoratology cover causes and treatments of neurotrauma, neurodegeneration, cerebrovascular anoxia or ischemia, edema, demyelination, sensory and motor disorders, and neuropathic pain, as well as neural damage resulting from toxic, physical and chemical factors, immune, infectious, inflammatory, hereditary, congenital, developmental, and other causes of neural injury. 5. Neurorestorative therapies include regeneration and reconstruction of nervous tissues by transplantation of tissue, cells, or biomaterials and bioengineering, modulation by electro-magnetic stimulation, pharmaceutical or chemical therapies, and combinations of the above. 6. Functional recovery is the objective of neurorestoratology, requiring close integration of neurorestorative and neurorehabilitative therapies, as well as the practice of clinical and preventative medicine to minimize complications of neural degeneration and damage. 7. Neurorestoratology recognizes the importance of small functional gains that have significant effects on quality of life. Neurorestoratology is interested in the mechanisms of spontaneous activity and enhancing this recovery. 8. Neurorestoratology supports the highest standards for clinical trials to evaluate the safety and efficacy of its neurorestorative therapies, the establishment of validated outcome measures, and ethical treatment of patients. 9. The International Association for Neurorestoratology will develop guidelines for neurorestorative therapies, seek and encourage development of new therapies, promote multi-center collaboration, and will contribute to the training of people in the field.

Clinical cell therapy guidelines for neurorestoration (China version 2016)

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