International Association Of Neurorestoratology Research Articles

Highlights for the 10th Annual Conference of the International Association of Neurorestoratology

The 10th annual conference of the International Association of Neurorestoratology (IANR) was held on Sept. 28-30, 2017. Here main promising topics were summarized, such as, memorial of Professor Geoffrey Raisman—Life Honorary President of IANR, highlights which include cell transplantation, new mechanism and new technology, problems and challenges in the field of Neurorestoratology.

Commemorating Geoffrey Raisman: a great neuroscientist and one of the founders of neurorestoratology and the IANR

Commemorating Geoffrey Raisman: a great neuroscientist and one of the founders of neurorestoratology and the IANR Ying Li,1 Pawel Tabakow,2 Daqing Li,1 Hongyun Huang3 On behalf of the International Association of Neurorestoratology 1Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK; 2Department of Neurosurgery, Wroclaw Medical University, Wroclaw, Poland; 3Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing, People’s Republic of China One year ago (January 27, 2017), the sad news that Life Honorary President of the International Association of Neurorestoratology (IANR), Geoffrey Raisman (Figure 1) had passed away shocked all our association members. We could hardly hide our grief. Besides expressing our grief and condolences to his wife, Vivian; his daughter, Ruth; and all his family, the Core Administration members communicated among each other via email and made a proposal to rename the Youth Forum of the Annual Conference, to the Raisman Youth Forum of the Annual Conference. The fourth IANR Council Board meeting in Argentina on September 29, 2017 approved this motion, and decided to establish the Raisman Neurorestoratology Foundation and to write an article commemorating him to be published in the Journal of Neurorestoratology. This commemorative article is divided into three parts: 1) his students and colleagues Daqing Li and Ying Li introduce his life and work; 2) his collaborating partner Pawel Tabakow introduces the process of their clinical trial; and 3) Hongyun Huang on behalf of the IANR introduces Geoffrey Raisman’s contribution to neurorestoratology and IANR. All individuals in the included images have provided written informed consent for the images to be published.&nbsp

Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)

Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version “Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)”. The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.

Consensus of clinical neurorestorative progress in patients with complete chronic spinal cord injury.

Currently, there is a lack of effective therapeutic methods to restore neurological function for chronic complete spinal cord injury (SCI) by conventional treatment. Neurorestorative strategies with positive preclinical results have been translated to the clinic, and some patients have gotten benefits and their quality of life has improved. These strategies include cell therapy, neurostimulation or neuromodulation, neuroprosthesis, neurotization or nerve bridging, and neurorehabilitation. The aim of this consensus by 31 experts from 20 countries is to show the objective evidence of clinical neurorestoration for chronic complete SCI by the mentioned neurorestorative strategies. Complete chronic SCI patients are no longer told, "nothing can be done." The clinical translation of more effective preclinical neurorestorative strategies should be encouraged as fast as possible in order to benefit patients with incurable CNS diseases. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer's and Parkinson's disease.

In view of the rapid preclinical development of cell-based therapies for neurodegenerative disorders, traumatic brain injury, and tumors, the safe and efficient delivery and targeting of therapeutic cells to the central nervous system is critical for maintaining therapeutic efficacy and safety in the respective disease models. Our previous data demonstrated therapeutically efficacious and targeted delivery of mesenchymal stem cells (MSCs) to the brain in the rat 6-hydroxydopamine model of Parkinson's disease (PD). The present study examined delivery of bone marrow-derived MSCs, macrophages, and microglia to the brain in a transgenic model of PD [(Thy1)-h[A30P] αS] and an APP/PS1 model of Alzheimer's disease (AD) via intranasal application (INA). INA of microglia in naive BL/6 mice led to targeted and effective delivery of cells to the brain. Quantitative PCR analysis of eGFP DNA showed that the brain contained the highest amount of eGFP-microglia (up to 2.1 × 10(4)) after INA of 1 × 10(6) cells, while the total amount of cells detected in peripheral organs did not exceed 3.4 × 10(3). Seven days after INA, MSCs expressing eGFP were detected in the olfactory bulb (OB), cortex, amygdala, striatum, hippocampus, cerebellum, and brainstem of (Thy1)-h[A30P] αS transgenic mice, showing predominant distribution within the OB and brainstem. INA of eGFP-expressing macrophages in 13-month-old APP/PS1 mice led to delivery of cells to the OB, hippocampus, cortex, and cerebellum. Both MSCs and macrophages contained Iba-1-positive population of small microglia-like cells and Iba-1-negative large rounded cells showing either intracellular amyloid β (macrophages in APP/PS1 model) or α-synuclein [MSCs in (Thy1)-h[A30P] αS model] immunoreactivity. Here, we show, for the first time, intranasal delivery of cells to the brain of transgenic PD and AD mouse models. Additional work is needed to determine the optimal dosage (single treatment regimen or repeated administrations) to achieve functional improvement in these mouse models with intranasal microglia/macrophages and MSCs. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

Intra-arterial delivery of human bone marrow mesenchymal stem cells is a safe and effective way to treat cerebral ischemia in rats.

Cerebral ischemic stroke is a very common condition that can cause death and disability. Studies have confirmed that stem cells have therapeutic effects if administered after a stroke. There is still a great deal of debate regarding the best route for cell transplantation. Intravascular delivery is the most commonly used one. In this study, the therapeutic effects of bone marrow stem cells (BMSCs) delivered by intra-arterial (IA) and intravenous (IV) injection in a rat transient middle cerebral artery occlusion model (MCAO) are compared. Histological analysis demonstrated that the IA route bypasses the pulmonary system and directs the cells to the ischemic parts of the brain more efficiently. The BMSCs delivered via the IA route promoted angiogenesis and improved functional recovery. The cerebral blood flow (CBF) of the rats was monitored during the IA injection process. No reduction in CBF or microstrokes was detected. Brain perfusion and metabolism, as evaluated by SPECT and PET, were better in rats treated with cells delivered via IA. Results showed that the IA route is a safe and effective way to transplant hBMSCs. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

To the novel paradigm of proteome-based cell therapy of tumors: through comparative proteome mapping of tumor stem cells and tissue-specific stem cells of humans.

We performed proteome mapping (PM), cataloging, and bioinformation analysis of protein lysates of human neural (CD133(+)) progenitor and stem cells (NPSCs) isolated from the olfactory sheath of a nose, multipotent mesenchymal (CD29(+), CD44(+), CD73(+), CD90(+), CD34(-)) stromal cells (MMSCs) isolated from human bone marrow, and tumor (CD133(+)) stem cells (TSCs) isolated from the human U87 glioblastoma (GB) cell line. We identified 1,664 proteins in the examined lysates of stem cells (SCs), 1,052 (63.2%) of which are identical in NPSCs and TSCs and 607 proteins (36.47%) of which are identical in MMSCs and TSCs. Other proteins in U87 GB TSCs are oncospecific or carcinogenesis associated. The biological processes, molecular functions, cell localization, and protein signal pathways of the proteins available in all three proteomes were annotated by PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), PANTHER (http://www.pantherdb.org/), GeneOntology (http://www.geneontology.org/), and KEGG (http://www.genome.jp/kegg/) databases. It was shown that gliomaspheres of U87 GB had only 10 intracellular signal transduction pathways (ISTP) that were not modified by the neoplastic process, but only two of them (integrin and focal adhesion pathways) were accessible for regulatory action on gene candidates in the TSC nucleus. Carcinogenesis-free membrane proteins, IPST, and genes expressing proteins of these pathways in U87 GB TSCs can be viewed as main targets for regulatory effects on TSCs. We offer a novel concept of proteome-based complex therapy of tumors. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

The potential of human umbilical cord-derived mesenchymal stem cells as a novel cellular therapy for multiple sclerosis.

Multiple sclerosis (MS) is a complex disease of neurological disability, affecting more than 300 out of every 1 million people in the world. The purpose of the study was to evaluate the therapeutic effects of human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation in MS patients. Twenty-three patients were enrolled in this study, and 13 of them were given hUC-MSC therapy at the same time as anti-inflammatory treatment, whereas the control patients received the anti-inflammatory treatment only. Treatment schedule included 1,000 mg/kg of methylprednisolone intravenously (IV) daily for 3 days and then 500 mg/kg for 2 days, followed by oral prednisone 1 mg/kg/day for 10 days. The dosage of prednisone was then reduced by 5 mg every 2 weeks until reaching a 5-mg/day maintenance dosage. Intravenous infusion of hUC-MSCs was applied three times in a 6-week period for each patient. The overall symptoms of the hUC-MSC-treated patients improved compared to patients in the control group. Both the EDSS scores and relapse occurrence were significantly lower than those of the control patients. Inflammatory cytokines were assessed, and the data demonstrated a shift from Th1 to Th2 immunity in hUC-MSC-treated patients. Our data demonstrated a high potential for hUC-MSC treatment of MS. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

Neural stem cell-conditioned medium protects neurons and promotes propriospinal neurons relay neural circuit reconnection after spinal cord injury.

Human fetal neural stem cells (hNSCs) are used to treat a variety of neurological disorders involving spinal cord injury (SCI). Although their mechanism of action has been attributed to cell substitution, we examined the possibility that NSCs may have neuroprotective activities. The present article studied the action of hNSCs on protecting neurons and promoting corticospinal tract (CST) axon regeneration after SCI. hNSCs were isolated from the cortical tissue of spontaneously aborted human fetuses. The cells were removed from the NSC culture medium to acquire NSCM, thus excluding the effect of cell substitution. Continuous administration of the NSCM after the SCI resulted in extensive growth of the CST in the cervical region and more than tripled the formation of synaptic contacts between CST collaterals and propriospinal interneurons that project from the cervical level of the spinal cord to the lumbar level. NSCM reduced the number of caspase 3-positive apoptotic profiles at 7 days and protected against loss of the neurons 6 weeks after injury. NSCM promoted locomotor recovery with a five-point improvement on the BBB scale in adult rats. Thus, hNSCs help to set up a contour neural circuit via secretory factors, which may be the mechanism for their action in SCI rats. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

First study of intra-arterial delivery of myogenic mononuclear cells to skeletal muscles in primates.

The main challenge of cell transplantation as a treatment of myopathies is the large amount of tissue to treat. Intravascular delivery of cells may be an ideal route if proven to be effective and safe. Given the importance of nonhuman primates for preclinical research in transplantation, we tested the intra-arterial injection of β-galactosidase (β-Gal)-labeled myoblasts in macaques. Cells were injected into one of the femoral arteries in seven monkeys. Some muscle sites were damaged concomitantly in three monkeys. Various organs and muscles were sampled 1 h, 1 day, 12 days, 3 weeks, and 5 weeks after transplantation. Samples were analyzed by histology. Most β-Gal(+) cells were observed in the capillaries and arterioles of muscles and other tissues of the leg homolateral to the cell injection. Groups of necrotic myofibers in the proximity of an arteriole plugged by a β-Gal(+) embolus were interpreted as microinfarcts. Scarce β-Gal(+) cells were observed in the lungs 1 h and 1 day posttransplantation. No β-Gal(+) cells were observed in other organs or muscles. β-Gal(+) myofibers were observed 12 days, 3 weeks, and 5 weeks after transplantation in muscles of the leg after the cell injection, in sites that were damaged at the time of cell injection. In conclusion, most intra-arterially injected myoblasts were retained in vessels of the leg homolateral to the cell injection site, and they fused with myofibers in regions in which there was a process of myofiber regeneration. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

The experimental therapy on brain ischemia by improvement of local angiogenesis with tissue engineering in the mouse.

Neural restoration has proven to be difficult after brain stroke, especially in its chronic stage. This is mainly due to the generation of an unpropitious niche in the injured area, including loss of vascular support but production of numerous inhibitors against neuronal regeneration. Reconstruction of a proper niche for promoting local angiogenesis, therefore, should be a key approach for neural restoration after stroke. In the present study, a new biomaterial composite that could be implanted in the injured area of the brain was created for experimental therapy of brain ischemia in the mouse. This composite was made using a hyaluronic acid (HA)-based biodegradable hydrogel scaffold, mixed with poly(lactic-co-glycolic acid) (PLGA) microspheres containing vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1), two factors that stimulate angiogenesis. In addition, the antibody of Nogo receptor (NgR-Ab), which can bind to multiple inhibitory myelin proteins and promote neural regeneration, was covalently attached to the hydrogel, making the hydrogel more bioactive and suitable for neural survival. This composite (HA-PLGA) was implanted into the mouse model with middle cerebral artery occlusion (MCAO) to explore a new approach for restoration of brain function after ischemia. A good survival and proliferation of human umbilical artery endothelial cells (HUAECs) and neural stem cells (NSCs) were seen on the HA hydrogel with PLGA microspheres in vitro. This new material was shown to have good compatibility with the brain tissue and inhibition to gliosis and inflammation after its implantation in the normal or ischemic brain of mice. Particularly, good angiogenesis was found around the implanted HA-PLGA hydrogel, and the mouse models clearly showed a behavioral improvement. The results in this present study indicate, therefore, that the HA-PLGA hydrogel is a promising material, which is able to induce angiogenesis in the ischemic region by releasing VEGF and Ang1, thus creating a suitable niche for neural restoration in later stages of stroke. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

Summary report of the International Association of Neurorestoratology VII Conference: regulations, ethics, science, and the need of patients care in neurorestoratology.

Summary Report of the International Association of Neurorestoratology VII Conference : Regulations, Ethics, Science, and the Need of Patients Care in Neurorestoratology

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

Neurorestoratology: one of the most promising new disciplines at the forefront of neuroscience and medicine Hongyun Huang,1 Hari Shanker Sharma2 1Department of Neurosurgery, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, People's Republic of China; 2Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, SwedenNeurorestoratology 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.

Standard Recommendations for the Application of Chinese Clinical Cell Therapy for Neurorestoration (2012)

Cell therapy has been shown to be a promising alternative therapy for neurorestoration, and more than 30 different types of cells have been shown to possess some capability to restore lost or damaged neurological functions. Chinese physicians have successfully applied cell therapy to many neurological diseases and damages in the clinic and contributed to establish a discipline of neurorestoratology. To standardize the clinical procedures of cell therapy as one of the strategies for treating neurological disorders, the Chinese Branch of the International Association of Neurorestoratology (IANR) and the Preparatory Committee of Chinese Association of Neurorestoratology recently completed the Standard Recommendations (2012) for the Application of Chinese Clinical Cell Therapy for Neurorestoration. We hope these recommendations will guide clinical practice in applying cell therapy for neurorestoration, which will therein offer a reference for both Chinese and other countries' governments to make relevant official regulations. 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 Transplantation in Six Patients with Chronic Complete Spinal Cord Injury

The aim of the study was to analyze the clinical efficacy and safety of olfactory ensheathing cell (OEC) transplantation for treating patients with chronic, complete spinal cord injury (SCI). Six patients with six chronic complete spinal cord injuries were recruited and treated with autologous OEC transplantation and followed for 24 months. The scores from before and after transplantation were analyzed. This was a self-control experiment. There was significant amelioration in the scores of the standard neurological classification of spinal cord injury made by the America Spinal Cord Injury Association (ASIA) and the International Association of Neurorestoratology-Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS) following OEC transplantation with 24 months of follow-up. No clinical complications were observed. OEC transplantation would appear to be clinically safe and may promote the neurofunctional recovery of SCI based on data from six patients. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

Control of Olfactory Ensheathing Cell Behaviors by Electrospun Silk Fibroin Fibers

Olfactory ensheathing cells (OECs), the only glial cell type that normally penetrates the transition zone between the peripheral and central nervous systems, are one of the most promising candidates for cell transplantation in repairing spinal cord injury (SCI). However, we must manipulate and regulate OECs' behavior to make these cells effective in cell transplantation. In the present study, we assessed the response of rat OECs to different variants of nanofibrous silk fibroin mats with regard to cell morphology, adhesion, proliferation, and migration and the related gene and protein expression. Results showed that OECs adhere and spread more easily on Tussah silk fibroin (TSF) fibers than Bombyx mori silk fibroin fibers, resulting in a higher rate of cell proliferation and gene and protein expression, examined by RT-PCR and ELISA. In addition, the morphology of OECs on microfibers is mainly polygonal with short protrusions, whereas the OECs on nanofibers exhibit a bipolar shape with long protrusions that align along the fibers, especially when aligned fibers are employed. Moreover, OECs on silk fibroin nanofibers migrate more efficiently than those on poly-L-lysine (PLL). Based on the experimental results, the morphology, adhesion, spread, gene and protein expression, and migration of OECs could be modulated and regulated by adjusting the contents and structure of silk fibroin nanofibers, shedding light on the control of OECs' behavior in nerve tissue engineering and thus the future therapeutic intervention for nerve repair after injury. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

A Clinical Study Shows Safety and Efficacy of Autologous Bone Marrow Mononuclear Cell Therapy to Improve Quality of Life in Muscular Dystrophy Patients

Muscular dystrophy is a genetic disorder with no definite cure. A study was carried out on 150 patients diagnosed with muscular dystrophy. These included Duchenne muscular dystrophy, limb-girdle muscular dystrophy, and Becker muscular dystrophy variants. They were administered autologous bone marrow-derived mononuclear cells intrathecally and intramuscularly at the motor points of the antigravity weak muscles followed by vigorous rehabilitation therapy. No significant adverse events were noted. Assessment after transplantation showed neurological improvements in trunk muscle strength, limb strength on manual muscle testing, gait improvements, and a favorable shift on assessment scales such as the Functional Independence Measure and the Brooke and Vignos Scales. Furthermore, imaging and electrophysiological studies also showed significant changes in selective cases. On a mean follow-up of 12 ± 1 months, overall 86.67% cases showed symptomatic and functional improvements, with six patients showing changes with respect to muscle regeneration and a decrease in fatty infiltration on musculoskeletal magnetic resonance imaging and nine showing improved muscle electrical activity on electromyography. Fifty-three percent of the cases showed an increase in trunk muscle strength, 48% showed an increase in upper limb strength, 59% showed an increase in lower limb strength, and approximately 10% showed improved gait. These data were statistically analyzed using Student's paired t test and found to be significant. The results show that this treatment is safe and efficacious and also improves the quality of life of patients having muscular dystrophy. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

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 SOD1(G93A) 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 SOD1(G93A) 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.

Cell Transplantation as a Pain Therapy Targets Both Analgesia and Neural Repair

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.

Multiple Cell Transplantation Based on an Intraparenchymal Approach for Patients with Chronic Phase Stroke

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.