Stem Cell Therapy for Stroke
The traditional definition of stroke, devised by the World Health Organization in the 1970s, is a “neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 hours”. This definition was supposed to reflect the reversibility of tissue damage and was devised for the purpose, with the time frame of 24 hours being chosen arbitrarily. The 24-hour limit divides stroke from transient ischemic attack, which is a related syndrome of stroke symptoms that resolve completely within 24 hours. With the availability of treatments that, when given early, can reduce stroke severity, many now prefer alternative concepts, such as brain attack and acute ischemic cerebrovascular syndrome (modeled after heart attack and acute coronary syndrome respectively), that reflect the urgency of stroke symptoms and the need to act swiftly.
Strokes can be classified into two major categories: ischemic and hemorrhagic. Ischemic strokes are those that are caused by interruption of the blood supply, while hemorrhagic strokes are the ones which result from rupture of a blood vessel or an abnormal vascular structure. About 87% of strokes are caused by ischemia, and the remainder by hemorrhage. Some hemorrhages develop inside areas of ischemia (“hemorrhagic transformation”). It is unknown how many hemorrhages actually start as ischemic stroke.
In an ischemic stroke, blood supply to part of the brain is decreased, leading to dysfunction of the brain tissue in that area. There are four reasons why this might happen:
- Thrombosis (obstruction of a blood vessel by a blood clot forming locally)
- Embolism (obstruction due to an embolus from elsewhere in the body, see below),
- Systemic hypoperfusion (general decrease in blood supply, e.g., in shock)
- Venous thrombosis.
Stroke without an obvious explanation is termed “cryptogenic” (of unknown origin); this constitutes 30-40% of all ischemic strokes.
CT scan showing an intracerebral hemorrhage with associated intraventricular hemorrhage.
Intracranial hemorrhage is the accumulation of blood anywhere within the skull vault. A distinction is made between intra-axial hemorrhage (blood inside the brain) and extra-axial hemorrhage (blood inside the skull but outside the brain). Intra-axial hemorrhage is due to intraparenchymal hemorrhage or intraventricular hemorrhage (blood in the ventricular system). The main types of extra-axial hemorrhage are epidural hematoma (bleeding between the dura mater and the skull), subdural hematoma (in the subdural space) and subarachnoid hemorrhage (between the arachnoid mater and pia mater). Most of the hemorrhagic stroke syndromes have specific symptoms (e.g., headache, previous head injury).
Signs and symptoms
Stroke symptoms typically start suddenly, over seconds to minutes, and in most cases do not progress further. The symptoms depend on the area of the brain affected. The more extensive the area of brain affected, the more functions that are likely to be lost. Some forms of stroke can cause additional symptoms. For example, in intracranial hemorrhage, the affected area may compress other structures. Most forms of stroke are not associated with headache, apart from subarachnoid hemorrhage and cerebral venous thrombosis and occasionally intracerebral hemorrhage.
Various systems have been proposed to increase recognition of stroke by patients, relatives and emergency first responders. A systematic review, updating a previous systematic review from 1994, looked at a number of trials to evaluate how well different physical examination findings are able to predict the presence or absence of stroke. It was found that sudden-onset face weakness, arm drift (i.e., if a person, when asked to raise both arms, involuntarily lets one arm drift downward) and abnormal speech are the findings most likely to lead to the correct identification of a case of stroke (+ likelihood ratio of 5.5 when at least one of these is present). Similarly, when all three of these are absent, the likelihood of stroke is significantly decreased. While these findings are not perfect for diagnosing stroke, the fact that they can be evaluated relatively rapidly and easily make them very valuable in the acute setting.
For people referred to the emergency room, early recognition of stroke is deemed important as this can expedite diagnostic tests and treatments. A scoring system called ROSIER (recognition of stroke in the emergency room) is recommended for this purpose; it is based on features from the medical history and physical examination.
One of the challenges in the treatment, after diagnosis and treatment of the acute incident, is the time frame to addressing the underlying penumbra and restoring function as quickly as possible. As all medical approaches are time sensitive with brain function, post stroke a number of options exist. Remember that stabilization of function is essential prior to beginning any therapy for rehabilitation.
During the last number of years there has been a substantial effort to begin rehab as quickly as possible. In the conventional settings however the use of “experimental” techniques has been limited. One example is the use of hyperbaric oxygen to use oxygen under pressure to return function to damaged areas. Clearly there is a body of evidence to suggest this should be a primary intervention, for a number of patients. Its limited by the availability and cost as insurances will not pay for “experimental” services.
In a similar light is the use of stem cells to seed the brain with new neurological potentials. In many neurological disorders it has been clearly seen as the necessary step to reestablish both lost connections and function. There is a misconnection that in order to achieve this phenomenon stem cells need to be surgically placed in the damaged areas. With proper adjuvant therapies, at the time of stem cell infusion, along with stimulation utilizing growth factors one can safely begin a neurological rehabilitation program. We do place the cells in the spinal canal and our comprehensive protocols enhance blood brain permeability allowing for increased seeding.
At World Stem Cells, LLC we have developed a set of protocols to address the patients post stroke needs, including modifications to utilize many adaptive aid, coupled with ongoing physical and occupational therapy, under the supervision of a board certified neurologist and staff.
Due to the nature of this disorder it is essential to address the stroke as soon as possible and make certain that you’re released and stable to fly. Only your neurologist should make this determination.
There is now a significant amount of published data that clearly indicates this therapy as appropriate and potentially life saving.
The studies have confirmed that an increased blood flow, in the ischemic areas, occurs within a few days after stroke and is associated with neurological recovery. The induction of new blood vessel formation (angiogenesis) has been reported with transplantation of stem cells, from the amplified growth factors in the damaged area. A neuroprotective effect occurs by the secretion of cytokines, chemical messengers stimulated by the new stem cells. Reductions in lesion size have been noted in a number of studies. Also reduced inflammation coupled with inhibition of an overactive immune response has been seen. Please see below for direct reference.
After a review of your medical records and discussions with medical staff, a protocol is designed especially for you. Specifics of your condition are addressed along with any special needs. It may be similar to the one illustrated below:
At the clinic you will be examined by our physicians. Information including any risks and expectations concerning your treatment, plus answers to any questions you may have will be addressed. A blood draw, to determine cell counts and other chemistries will be collected and cell expansion medication may be administered. Then you will return to your hotel for a restful day or a good nights sleep.
At the clinic our physician/s will review the laboratory results, determine if the cell count is within range, and discuss the response to the stimulation. They may or may not provide additional cell expansion medications and may add adjunctive treatments. The levels of your response will determine if you would return to the hotel, with little restriction on your activities, or possibly go forward with harvesting and processing your cells.
If the cell count and viability is appropriate for harvest either a bone marrow or adipose collection will be utilized. We typically use local anesthetics for adults and general anesthesia for youngsters. The entire procedure normally takes less than 30 minutes. Although some pain is felt when the needle is inserted, most patients do not find the bone marrow or adipose collection procedure particularly painful.
We recently placed a number of videos on our website interviewing our patient’s who discuss the procedure and their lack of discomfort.
After the collection you may return to the hotel, with some restrictions. The bone marrow or adipose collected is processed in our contract State-Of-Art laboratory by trained staff, under the supervision of the lab physician.
As an alternative to the above, cord blood may be used based on the patient’s individual medical condition and options.
At the clinic or at the hospital you will be treated by IV infusion and/or a lumbar puncture, which injects the stem cells into the cerebrospinal fluid. This route transports the cells into the spinal canal and the brain directly influencing the nervous systems, thereby eliminating the brain/blood barrier. If a lumbar puncture is performed, the patient will be required to restrict their activities and potentially spend the day in the hospital or at their hotel.
At the clinic or hospital the patient will receive a post-treatment examination and evaluation prior to their release. Additional therapy and treatments may also be utilized to maximize the placement and activities of the procedure.
Day 6: Optionally there may be the use of additional ancillary therapies to enhance the procedure.
What makes our treatment different ?
Our approach includes stimulation, prior to collection, processing and expansion of the cell along with the use of growth factors, together with an integrated medical approach. This maximizes the growth and implantation potentials yielding optimized potentials of making changes in your disease.
Our staff physicians are all board certified, in their field with years of experience. Your team includes both primary and ancillary care professionals devoted to maximizing your benefits from the procedures. We enroll you in an open registry to track your changes independently, for up to 20 years.
As our patient we also keep you abreast of the newest developments in stem cell research. This is an ongoing relationship to maintain and enhance your health.
Our promise is to provide you with travel and lodging support, access to bilingual staff members throughout the entire process and most importantly the best medical care possible.
Another resource for stroke patients is the BCenter.com for Patient Stroke advocacy. Valerie Greene, a stroke survivor, has launched a option rich site for those having experienced a stroke.
This is a rapidly expanding set of materials that illustrates the many years of experience that clearly suggest the safe and effective means of addressing stroke patients. I have placed highlights in areas of the study that I feel are substantial and warrant the readers consideration.
Our stroke patients responses have exceeded our expectations, multiple times and we continue to address this emerging field with newer and more effective treatments.
Stroke repair with cell transplantation: neuronal cells, neuroprogenitor cells, and stem cells Kondziolka D, Wechsler L. Neurosurg Focus. 2008; 24 (3-4):E13
Stroke is a common cause of death and disability. The role of cellular transplantation to promote functional recovery has been explored. Preclinical studies first established the potential for cultured neuronal cells derived from a teratocarcinoma cell line to be tested for safety and efficacy in the treatment of human stroke. In animal models of stroke that caused reproducible learning and motor deficits, injection of neuronal cells resulted in a return of learning behavior retention time and motor function. In this report the authors review several current concepts for cellular repair, discuss important patient selection and surgical technique issues, and discuss plans for future experiments.
Bone marrow appears to be a promising source of cells for restorative medicine.20 Numerous studies on the role of stromal cells in traumatic brain injury have been published by Li et al. and Mahmood et al. SanBio 623 cells are human bone marrow–derived neuroprogenitor cells under development by SanBio Inc. as an allogenic cell therapy for chronic, stable stroke and other neurodegenerative conditions.
Intravenous Administration of Auto Serum-expanded Autologous Mesenchymal Stem Cells in Stroke Osamu Honmou; et al Posted: 06/30/2011; Brain. 2011;134(6):1790-1807. © 2011 Oxford University Press
Transplantation of human mesenchymal stem cells has been shown to reduce infarct size and improve functional outcome in animal models of stroke. Here, we report a study designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells expanded in autologous human serum in stroke patients. We report an unblinded study on 12 patients with ischaemic grey matter, white matter and mixed lesions, in contrast to a prior study on autologous mesenchymal stem cells expanded in foetal calf serum that focused on grey matter lesions. Cells cultured in human serum expanded more rapidly than in foetal calf serum, reducing cell preparation time and risk of transmissible disorders such as bovine spongiform encephalomyelitis. Autologous mesenchymal stem cells were delivered intravenously 36–133 days post-stroke. All patients had magnetic resonance angiography to identify vascular lesions, and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. Magnetic resonance perfusion-imaging and 3D-tractography were carried out in some patients. Neurological status was scored using the National Institutes of Health Stroke Scale and modified Rankin scores. We did not observe any central nervous system tumours, abnormal cell growths or neurological deterioration, and there was no evidence for venous thromboembolism, systemic malignancy or systemic infection in any of the patients following stem cell infusion. The median daily rate of National Institutes of Health Stroke Scale change was 0.36 during the first week post-infusion, compared with a median daily rate of change of 0.04 from the first day of testing to immediately before infusion. Daily rates of change in National Institutes of Health Stroke Scale scores during longer post-infusion intervals that more closely matched the interval between initial scoring and cell infusion also showed an increase following cell infusion. Mean lesion volume as assessed by magnetic resonance imaging was reduced by >20% at 1 week post-cell infusion. While we would emphasize that the current study was unblinded, did not assess overall function or relative functional importance of different types of deficits, and does not exclude placebo effects or a contribution of recovery as a result of the natural history of stroke, our observations provide evidence supporting the feasibility and safety of delivery of a relatively large dose of autologous mesenchymal human stem cells, cultured in autologous human serum, into human subjects with stroke and support the need for additional blinded, placebo-controlled studies on autologous mesenchymal human stem cell infusion in stroke.
Optimizing the Success of Cell Transplantation Therapy for Stroke Tonya M. Bliss, Robert H. Andres, and Gary K. Steinberg Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, USA
Stem cell transplantation has evolved as a promising experimental treatment approach for stroke. In this review, we address the major hurdles for successful translation from basic research into clinical applications and discuss possible strategies to overcome these issues. We summarize the results from present pre-clinical and clinical studies and focus on specific areas of current controversy and research: (i) the therapeutic time window for cell transplantation; (ii) the selection of patients likely to benefit from such a therapy; (iii) the optimal route of cell delivery to the ischemic brain; (iv) the most suitable cell types and sources; (v) the potential mechanisms of functional recovery after cell transplantation; and (vi) the development of imaging techniques to monitor cell therapy.
Conclusions: The pre-clinical evidence shows great promise for cell transplantation as a therapy for stroke. While we can be cautiously optimistic about the reality of such a therapy, many fundamental questions related to the optimal patient (including age, sex, etiology, anatomic location and size of infarct, and medical history), the most appropriate cell type, cell dose, the timing of surgery, the route and site of delivery, the need for immunosuppression, and mechanism of action remain to be answered.
Autologous mesenchymal stem cell transplantation in Stroke Patients Oh Young Bang MD, PhD etal Ann Neurol 2005;57:874–882
We examined the feasibility, efficacy, and safety of cell therapy using culture-expanded autologous MSCs in patients with ischemic stroke. We prospectively and randomly allocated 30 patients with cerebral infarcts within the middle cerebral arterial territory and with severe neurological deficits into one of two treatment groups: the MSC group (n = 5) received intravenous infusion of 1 × 108 autologous MSCs, whereas the control group (n = 25) did not receive MSCs. Changes in neurological deficits and improvements in function were compared between the groups for 1 year after symptom onset. “Outcomes improved in MSC-treated patients compared with the control patients and of the MSC group improved consistently during the follow-up period.” Serial evaluations showed no adverse cell-related, serological, or imaging-defined effects. In patients with severe cerebral infarcts, the intravenous infusion of autologous MSCs appears to be a feasible and safe therapy that may improve functional recovery.
Stem Cell Treatment for Stroke Survivors
One of the latest studies being funded by the National Institutes of Health is based out of the University of Texas at Houston. The study aims to use a patient’s own stem cells harvested from bone marrow to repair the brain as quickly as possible after the stroke episode (within 24-72 hours of initial symptoms). If effective, it will help to reduce disability incurred due to brain damage. As of April 2009, at least one patient has undergone this stem cell treatment with encouraging preliminary results.
This clinical study builds on laboratory and animal research which indicated that stem cells can migrate to the injured area of the brain and help repair damage. The prior research showed that, while the stem cells did not generate new brain cells as the scientists had hypothesized, they did cause the cells to protect nerve tissue from damage due to inflammation. When the scientists compared results to the animals that did not receive the injected cells, they found that the animals who received the stem cell therapy showed 60% less nerve tissue damage.
A similar study was conducted at Stanford University in California in 2008, where animals’ brains were injected with neural tissue derived from human embryonic stem cells. In this study, the animals demonstrated improved mobility and strength in the parts of their bodies affected by the stroke.
Bone marrow stromal cells as replacement cells for Parkinson’s disease: generation of an anatomical but not functional neuronal phenotype.
Parkinson’s Centre, Edith Cowan University, Perth, Western Australia; School of Exercise Biomedical and Health Science, Edith Cowan University, Perth, Western Australia, Australia. email@example.com
The focus of cell replacement therapies (CRTs) for Parkinson’s disease has been on delivering dopamine-producing cells to the striatum. Fetal grafts have proven the feasibility of this approach, but an appropriate source of replacement cells has restricted the clinical translation. Bone marrow stromal cells (BMSCs) have been heralded as an ideal source of dopaminergic (DAergic) replacement cells, as they are viewed as ethically acceptable, easily procured, and readily expanded. It is known that they confer functional benefits, particularly in stroke models, through the release of neurotrophic factors, but their transdifferentiation into neurons is still under contention. We sought to evaluate the neuronal phenotype and functional capacity of adult rat BMSCs after exposure to a novel multistep in vitro differentiation protocol compared with cells exposed to other reported neuronal differentiation conditions. We employed a systematic, comprehensive method of assessment to determine the neuronal differentiation capacity of BMSCs. Our fluorescence-activated cell sorting, immunofluorescent and semiquantitative polymerase chain reaction results confirmed that undifferentiated BMSCs isolated based on their adherence to plastic are of mesenchymal origin and express a range of lineage markers. After exposure to preinduction and neuronal induction steps, BMSCs down-regulate markers of other lineages but fail, as assessed by patch clamp, to differentiate into functional neurons. Thus, for BMSCs to be considered a source of DAergic neuronal replacement cells, their ability to transdifferentiate terminally along a neuronal lineage first must be clarified before attempting to direct more complex specification process required for them to be used in Parkinson’s-disease-focused CRTs.
Crown Copyright © 2011. Published by Mosby, Inc. All rights reserved.
The great migration of bone marrow-derived stem cells toward the ischemic brain: Therapeutic implications for stroke and other neurological disorders.
Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, United States.
Accumulating laboratory studies have implicated the mobilization of bone marrow (BM)-derived stem cells in brain plasticity and stroke therapy. This mobilization of bone cells to the brain is an essential concept in regenerative medicine. Over the past ten years, mounting data have shown the ability of bone marrow-derived stem cells to mobilize from BM to the peripheral blood (PB) and eventually enter the injured brain. This homing action is exemplified in BM stem cell mobilization following ischemic brain injury. Various BM-derived cells, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and very small embryonic-like cells (VSELs) have been demonstrated to exert therapeutic benefits in stroke. Here, we discuss the current status of these BM-derived stem cells in stroke therapy, with emphasis on possible cellular and molecular mechanisms of action that mediate the cells’ beneficial effects in the ischemic brain. When possible, we also discuss the relevance of this therapeutic regimen in other central nervous system (CNS) disorders.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia Experimental Neurology, Volume 199, Issue 1, May 2006, Pages 56-66T. Honma, O. Honmou, S. Iihoshi, K. Harada, K. Houkin, H. Hamada and J.D. Kocsis
Time course and outcome of recovery from stroke: Relevance to stem cell treatment GILMAN Department of Neurology, University of MichiganExperimental neurology 2006, vol. 199, no 1 pp. 37-41
Current Clinical Neurology Vascular Dementia Cerebrovascular Mechanisms and Clinical Management 10.1385/1-59259-824-2:331 Robert H. Paul, Ronald Cohen, Brian R. Ott and Stephen Salloway Marc Fisher6 and Magdy Selim
Stem cell sources and therapeutic approaches for central nervous system and neural retinal disorders Journal of Neurosurgery March 2008 vol 24 no 3-4 Diana Yu, B.S.1, and Gabriel A. Silva, Ph.D.Departments of Bioengineering and 2Ophthalmology, and 3Neurosciences Program, University of California, San Diego, California
Adult stem cell therapy in stroke. S Haas, N Weidner, J Winkler Curr Opin Neurol (2005) 18: 59-64.
Therapeutic Potential of Neurotrophic Factors and Neural Stem Cells Against Ischemic Brain Injury Koji Abe Journal of Cerebral Blood Flow & Metabolism (2000) 20, 1393–1408;
Manipulation of endogenous neural stem cells following ischemic brain injury Pathophysiol Leker RR Thromb 2006;35 (1-2):58-62 Department of Neurology, Peritz Scheinberg Cerebrovascular Research Laboratory and the Agnes Ginges Center for Human Neurogenetics.
From bench to bedside: should we believe in the efficacy of stem cells in cerebral ischaemia? Morphologie. 2005 Sep;89(286):154-67 Tran-Dinh A, Kubis N. Centre de Recherche Cardiovasculaire, INSERM U689, Hôpital Lariboisière, Paris.
Stroke research priorities for the next decade – a representative view of the European scientific community. Cerebrovasc Dis. 2007;23(4):318-9; Meairs S, Wahlgren N, Dirnagl U, Lindvall O, Rothwell P, Baron JC, Hossmann K, Engelhardt B, Ferro J, McCulloch J, Kaste M, Endres M, Koistinaho J, Planas A, Vivien D, Dijkhuizen R, Czlonkowska A, Hagen A, Evans A, De Libero G, Nagy Z, Rastenyte D, Reess J, Davalos A, Lenzi GL, Amarenco P, Hennerici M Fadini GP, Agostini C, Avogaro A.
Endothelial progenitor cells in cerebrovascular disease. Stroke. 2005 Jan;36(1):151-3.
Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest. 2004 Aug;114(3):330-8 Taguchi A, Soma T, Tanaka H, Kanda T, Nishimura H, Yoshikawa H, Tsukamoto Y, Iso H, Fujimori Y, Stern DM, Naritomi H, Matsuyama T Department of Cerebrovascular Disease, National Cardiovascular Center, Osaka, Japan.
Transplantation for stroke Neurol Res. 2004 Apr;26(3):256-64. Roitberg B. Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL, USA. Regenerative t herapy for stroke. Chang YC Shyu WC Lin SZ Li H Cell Transplant 2007; 16 (2) ; 171-81
Cell replacement therapy for intracerebral hemorrhage Andres R, Guzman R, et al Neurosurg Focus. 2008; 24 (3-4):E16.
Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction.
Increasing evidence shows that administration of bone marrow mononuclear cells (BMMCs) is a potential treatment for various ischemic diseases, such as ischemic stroke. Although angiogenesis has been considered primarily responsible for the effect of BMMCs, their direct contribution to endothelial cells (ECs) by being a functional elements of vascular niches for neural stem/progenitor cells (NSPCs) has not been considered. Herein, we examine whether BMMCs affected the properties of ECs and NSPCs, and whether they promoted neurogenesis and functional recovery after stroke. We compared i.v. transplantations 1 x 10(6) BMMCs and phosphate-buffered saline in mice 2 days after cortical infarction. Systemically administered BMMCs preferentially accumulated at the postischemic cortex and peri-infarct area in brains; cell proliferation of ECs (angiogenesis) at these regions was significantly increased in BMMCs-treated mice compared with controls. We also found that endogenous NSPCs developed in close proximity to ECs in and around the poststroke cortex and that ECs were essential for proliferation of these ischemia-induced NSPCs. Furthermore, BMMCs enhanced proliferation of NSPCs as well as ECs. Proliferation of NSPCs was suppressed by additional treatment with endostatin (known to inhibit proliferation of ECs) following BMMCs transplantation. Subsequently, neurogenesis and functional recovery were also promoted in BMMCs-treated mice compared with controls. These results suggest that BMMCs can contribute to the proliferation of endogenous ischemia-induced NSPCs through vascular niche regulation, which includes regulation of endothelial proliferation. In addition, these results suggest that BMMCs transplantation has potential as a novel therapeutic option in stroke treatment.
Endothelial cells support survival, proliferation, and neuronal differentiation of transplanted adult ischemia-induced neural stem/progenitor cells after cerebral infarction.
Department of Cerebrovascular Disease, National Cardiovascular Center, Osaka, Japan. firstname.lastname@example.org
Transplantation of neural stem cells (NSCs) has been proposed as a therapy for a range of neurological disorders. To realize the potential of this approach, it is essential to control survival, proliferation, migration, and differentiation of NSCs after transplantation. NSCs are regulated in vivo, at least in part, by their specialized microenvironment or “niche.” In the adult central nervous system, neurogenic regions, such as the subventricular and subgranular zones, include NSCs residing in a vascular niche with endothelial cells. Although there is accumulating evidence that endothelial cells promote proliferation of NSCs in vitro, there is no description of their impact on transplanted NSCs. In this study, we grafted cortex-derived stroke-induced neural stem/progenitor cells, obtained from adult mice, onto poststroke cortex in the presence or absence of endothelial cells, and compared survival, proliferation, and neuronal differentiation of the neural precursors in vivo. Cotransplantation of endothelial cells and neural stem/progenitor cells increased survival and proliferation of ischemia-induced neural stem/progenitor cells and also accelerated neuronal differentiation compared with transplantation of neural precursors alone. These data indicate that reconstitution of elements in the vascular niche enhances transplantation of adult neural progenitor cells.
Autologous mesenchymal stem cell transplantation in stroke patients
- Oh Young Bang MD, PhD, Jin Soo Lee MD, Phil Hyu Lee MD, PhD, Gwang Lee PhD
Article first published online: 31 MAY 2005
Annals of Neurology Volume 57, Issue 6, pages 874–882, June 2005
Mesenchymal stem cell (MSC) transplantation improves recovery from ischemic stroke in animals. We examined the feasibility, efficacy, and safety of cell therapy using culture-expanded autologous MSCs in patients with ischemic stroke. We prospectively and randomly allocated 30 patients with cerebral infarcts within the middle cerebral arterial territory and with severe neurological deficits into one of two treatment groups: the MSC group (n = 5) received intravenous infusion of 1 × 108 autologous MSCs, whereas the control group (n = 25) did not receive MSCs. Changes in neurological deficits and improvements in function were compared between the groups for 1 year after symptom onset. Neuroimaging was performed serially in five patients from each group. Outcomes improved in MSC-treated patients compared with the control patients: the Barthel index (p = 0.011, 0.017, and 0.115 at 3, 6, and 12 months, respectively) and modified Rankin score (p = 0.076, 0.171, and 0.286 at 3, 6, and 12 months, respectively) of the MSC group improved consistently during the follow-up period. Serial evaluations showed no adverse cell-related, serological, or imaging-defined effects. In patients with severe cerebral infarcts, the intravenous infusion of autologous MSCs appears to be a feasible and safe therapy that may improve functional recovery.
Ann Neurol 2005;57:874–882