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Clinical Trials |

Safety and Immunological Effects of Mesenchymal Stem Cell Transplantation in Patients With Multiple Sclerosis and Amyotrophic Lateral Sclerosis FREE

Dimitrios Karussis, MD, PhD; Clementine Karageorgiou, MD; Adi Vaknin-Dembinsky, MD, PhD; Basan Gowda-Kurkalli, PhD; John M. Gomori, MD; Ibrahim Kassis, MSc; Jeff W. M. Bulte, PhD; Panayiota Petrou, MD; Tamir Ben-Hur, MD, PhD; Oded Abramsky, MD, PhD; Shimon Slavin, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, Laboratory of Neuroimmunology and Agnes Ginges Center for Neurogenetics and Multiple Sclerosis Center (Drs Karussis, Vaknin-Dembinsky, Petrou, Ben-Hur, and Abramsky and Mr Kassis), Department of Bone Marrow Transplantation (Drs Gowda-Kurkalli and Slavin), and Unit of Neuroradiology, Department of Radiology (Dr Gomori), Hadassah Hebrew University Hospital, Jerusalem, Israel; Department of Neurology, Gennimatas General Hospital, Athens, Greece (Dr Karageorgiou); and Russell H. Morgan Department of Radiology and Radiological Science, Department of Biomedical Engineering, and Department of Chemical and Biomolecular Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland (Dr Bulte).


Section Editor: Ira Shoulson, MD

More Author Information
Arch Neurol. 2010;67(10):1187-1194. doi:10.1001/archneurol.2010.248.
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Published online

Objective  To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

Design  A phase 1/2 open-safety clinical trial.

Patients  Fifteen patients with MS (mean [SD] Expanded Disability Status Scale [EDSS] score, 6.7 [1.0]) and 19 with ALS (mean [SD] Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS] score, 20.8 [8.0]) were enrolled.

Intervention  After culture, a mean (SD) of 63.2 × 106 (2.5 × 106) MSCs was injected intrathecally (n = 34) and intravenously (n = 14). In 9 cases, MSCs were magnetically labeled with the superparamagnetic iron oxide ferumoxides (Feridex).

Main Outcome Measures  The main outcome measure was the recording of side effects. Follow-up (≤25 months) included adverse events evaluation, neurological disability assessment by means of the EDSS, magnetic resonance imaging to exclude unexpected pathologies and track the labeled stem cells, and immunological tests to assess the short-term immunomodulatory effects of MSC transplantation.

Results  Twenty-one patients had injection-related adverse effects consisting of transient fever, and 15 reported headache. No major adverse effects were reported during follow-up. The mean ALSFRS score remained stable during the first 6 months of observation, whereas the mean (SD) EDSS score improved from 6.7 (1.0) to 5.9 (1.6). Magnetic resonance imaging visualized the MSCs in the occipital horns of the ventricles, indicating the possible migration of ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord. Immunological analysis revealed an increase in the proportion of CD4+CD25+ regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40+, CD83+, CD86+, and HLA-DR on myeloid dendritic cells at 24 hours after MSC transplantation.

Conclusion  Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects.

Trial Registration  clinicaltrials.gov Identifier: NCT00781872

Figures in this Article

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that leads to cumulative and irreversible CNS damage.13 Over time, therapeutic approaches to MS were aimed at suppressing the immune system to control the inflammatory process that causes the demyelination and axonal damage.2,3 However, the MS treatments available to date are only partially effective, especially in the progressive phases of the disease.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects motor neurons in the brain and spinal cord, leading to bulbar, respiratory, and limb weakness. There is no effective treatment, and the disease usually progresses to death within 2 to 4 years.4

Previous efforts using various neuroprotective agents in progressive MS and ALS did not prove successful. The use of multipotential stem cells may provide an alternative solution because stem cells can migrate locally into damaged CNS areas where they have the potential to support local neurogenesis or myelogenesis through neurotrophic effects, stimulation of resident CNS stem cells, induction of in situ immunomodulation, or, theoretically, even transdifferentiation.

Mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) are bone marrow–derived stem cells that normally generate osteocytes, adipocytes, and chondrocytes.5,6 Mesenchymal stem cells have been shown to possess immunomodulating properties, inducing suppression of various immune cell populations.714 Mesenchymal stem cells cultivated under different culture manipulations (chemical induction or use of growth factors) can give rise to neural-like, glial-like, and astrocytic-like cells in vitro.1519 In rats with an induced focal demyelinated lesion of the spinal cord, intravenous or intracerebral injection of MSCs resulted in remyelination.20,21 In the animal model of MS, experimental autoimmune encephalomyelitis, intravenous injection of MSCs into C57BL/6J mice was shown to downregulate the clinical severity of the disease with a parallel suppression of CNS inflammation through induction of T-cell anergy and decrease of demyelination.2225 Mesenchymal stem cells migrated into the CNS, where they promoted brain-derived neurotrophic factor production and induced proliferation of a limited number of oligodendrocyte progenitors. In our previous study,25 intraventricularly injected MSCs migrated to the white matter lesions in correlation with the degree of inflammation and induced neuroprotection, with preservation of the axons.25 Similar beneficial clinical effects of MSC transplantation were described in models of stroke and trauma.26

Clinical trials have revealed the feasibility and safety of the clinical use of MSCs (for review, see Giordano et al27) and have provided some evidence of efficacy in various medical conditions.2834

On the basis of the preclinical experience and the cumulative data from clinical studies,2839 we initiated an exploratory trial with autologous bone marrow–derived MSCs in 34 patients with intractable MS or progressive ALS. We combined intrathecal and intravenous administration to maximize the potential therapeutic benefit by accessing the CNS through the cerebrospinal fluid and the systemic circulation. In 9 patients, MSCs were labeled with the superparamagnetic iron oxide magnetic resonance imaging (MRI) contrast agent ferumoxides (Feridex)4043 to track cell migration after local grafting.

DESIGN OF TRIAL AND PATIENT POPULATION

This study, designed as a phase 1/2 open-safety clinical trial, was approved by the ethics committees of the Gennimatas General Hospital and Hadassah Hebrew University Hospital and registered in the National Institutes of Health database. We included 15 consenting patients with MS (7 men and 8 women; mean age, 35.3 [8.6] years) with a mean disease duration of 10.7 (2.9) (range, 5-15) years and baseline Expanded Disability Status Scale (EDSS) score of 6.7 (1.0) (range, 4.0-8.0), and we also included 19 patients with ALS (10 men and 9 women; (mean age, 53.0 [11.2] years) with a disease duration of 34.3 (20.6) (range, 6-84) months and a mean baseline Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score of 20.8 (8.0). (Unless otherwise indicated, data are given as mean (SD).) All patients signed an informed consent approved by the institutional review boards of both centers.

MS Inclusion Criteria

Consenting patients fulfilled the following 4 inclusion criteria for this study: (1) the clinical criteria of Poser et al44 for definite MS; (2) men and nonpregnant women aged 25 to 65 years; (3) duration of disease longer than 5 years; and (4) failure to respond to the currently available and registered agents for MS (ie, interferons, glatiramer acetate [Copaxone], and immunosuppressors), as manifested by an increase of at least 1 degree in the EDSS score during the past year or the appearance of at least 2 major MS relapses during the same period. We excluded MS patients (1) who were treated with cytotoxic medications (ie, cyclophosphamide, mitoxantrone, and azathioprine) during the 3 months before the trial; (2) who had significant cardiac, renal, or hepatic failure or any other disease that may interfere with the ability to interpret the results of the study; (3) who had an active infection; and (4) who showed severe cognitive decline or were unable to understand and sign the informed consent.

ALS Inclusion Criteria

Consenting patients fulfilled the following 3 inclusion criteria for this study: (1) meeting the El Escorial criteria for definite ALS45; (2) being men or nonpregnant women aged 25 to 65 years; and (3) having a progressive course, with evidence of deterioration of at least 5 degrees in the ALSFRS scale of disease severity during the year preceding inclusion in the trial. We excluded ALS patients with (1) high protein levels or lymphocytosis in the cerebrospinal fluid; (2) positive test results for anti-GM1 antibodies; (3) significant conduction blocks or slow conduction velocities (a reduction of >30%) in nerve conduction studies; (4) significant cardiac, renal, or hepatic failure or any other disease that may interfere with the ability to interpret the results of the study; (5) an active infection; and (6) cognitive decline or the inability to understand and sign the informed consent.

TREATMENT PROTOCOL
Bone Marrow Aspiration

Bone marrow aspiration was performed under short general anesthesia with puncture from the posterior superior iliac crest while the patient was lying in a left or a right lateral position. Approximately 200 mL of bone marrow inocula was obtained from each patient.

MSC Preparation and Culture

A culture of purified MSCs was prepared under aseptic conditions (positively pressurized clean rooms) using filtered sterilized Dulbecco modified Eagle medium with low glucose levels (Qiagen, Valencia, California) supplemented with 10% fetal bovine serum, 1% L-glutamine, and 1% penicillin-streptomycin-nystatin solution (all from Biological Industries, Kibbutz Beit-Haemek, Israel).

Mesenchymal cells were cultured for 40 to 60 days, until they reached confluency, and were then harvested and cryopreserved in 10% dimethyl sulfoxide–containing medium in liquid nitrogen (−196°C). At 2 weeks, a sample was taken for sterility testing and quality control. After sterility was confirmed, the MSCs were transferred to the laboratory on dry ice, thawed in a 37°C water bath, and washed twice with normal saline solution to remove any residual dimethyl sulfoxide. The cells were then resuspended in normal saline at a concentration of 10 × 106/mL to 15 × 106/mL. Two-thirds of the total number of cells (usually 60 × 106 to 100 × 106) were injected intrathecally, and one-third was injected intravenously. A sample of the cells to be injected was tested by fluorescence-activated cell sorter (FACS) analysis; cells consistently (>98%) expressed the surface markers characteristic of MSCs (CD29, CD73, CD90, CD105, and CD166) and were negative for CD34, CD45, and CD14.

Treatment Protocol

All patients received an intrathecal injection via a standard lumbar puncture. Patients with MS received a mean of 63.2 × 106 (2.5 × 106) cells; patients with ALS received 54.7 × 106 (17.4 × 106) cells in 2 mL of normal saline solution. Fourteen patients (5 with MS and 9 with ALS) also received intravenous MSCs (mean, 24.5 × 106 [2.5 × 106] for MS and 23.4 × 106 [6.0 × 106 ] for ALS, in 2 mL of normal saline solution). Nine patients received MSCs incubated with superparamagnetic iron oxide (ferumoxides) to detect their trafficking and migration by MRI. To this end, ferumoxides was complexed with the cationic polymer poly-L-lysine, and the cells were incubated for 24 to 48 hours as described in detail elsewhere.46

MAGNETIC RESONANCE IMAGING

We performed MRI on all patients within 4 to 48 hours after MSC infusion and again after 1 month and 3 to 6 months. The MRI examinations were used to exclude unexpected pathologies and also to track the CNS homing of injected MSCs in patients whose cells were labeled with ferumoxides. All MRIs were performed at 1.5 T with the exception of one performed at 3 T. Brain imaging was performed using standard T1-, T2-, diffusion-, and postgadolinium T1–weighted sequences. Whole spine imaging was performed using standard T1-, T2-, and postgadolinium T1–weighted sequences.

IMMUNOLOGICAL EVALUATION

Immunological analysis of lymphocyte subsets and cytokine production was performed in 12 patients (5 with ALS and 7 with MS, all of them undergoing intrathecal and intravenous transplantation) at baseline and 4 and 24 hours after MSC administration. The tests are described in the following paragraphs.

FACS Analysis of Lymphocyte Subsets

Peripheral blood monocytes were centrifuged using gradient cell separation medium (Histopaque 1077; Sigma-Aldrich Corp, St Louis, Missouri) and stained for flow cytometric analysis with anti-CD4 phycoerythrin (PE) and CD25–fluorescein isothiocyanate conjugate (FITC) (BD Biosciences, Mountain View, California). The isolated peripheral blood monocytes were also stained for the following myeloid dendritic markers: lineage cocktail FITC (BD Biosciences), CD11c antigen-presenting cells (Biotest Pharmaceuticals, Boca Raton, Florida), CD86 PE, CD83 PE, CD40 PE, and HLA-DR PE (eBioscience Inc, San Diego, California). The data were analyzed with the aid of a flow cytometer (Beckman Coulter, Brea, California).

Lymphocyte Proliferation in Response to Phytohemagglutinin

The assay was performed in 96-well, flat-bottom plates (Nunc plates; Danyel Biotech, Rehovot, Israel). Lymphocytes were isolated from whole blood by centrifugation using the gradient cell separation medium and seeded at 25 × 105/well in a mixture of RPMI (Roswell Park Memorial Institute) tissue culture medium, 10% fetal calf serum, 1mM glutamine, and penicillin-streptomycin (Biological Industries) and stimulated with the lectin phytohemagglutinin, 1 μg/mL (Sigma-Aldrich Corp). Cultures were incubated for 48 hours in a humidified atmosphere of 5% carbon dioxide at 37°C, and then proliferation was assayed using 1 μCi/well of tritiated thymidine (Amersham, Aylesbury, England) uptake. After 18 hours of incubation with tritiated thymidine, the cells were frozen in −20°C and then harvested on fiberglass filters using a cell harvester (Skatron Instruments, Lier, Norway); radioactivity was measured by a standard scintillation technique. The stimulation index was calculated as the ratio of the activated to the nonactivated cells.

SAFETY AND CLINICAL EFFECTS OF MSC TRANSPLANTATION
Safety

Of the 34 patients, 21 had a mild self-limited febrile reaction (temperature, ≤37.5°C) that lasted for 8 to 24 hours after MSC injection (Table 1). Headaches, which lasted for up to 7 days, were reported in 15 patients and were mainly related to the lumbar puncture. Meningeal irritation and aseptic meningitis was observed in 1 patient, and a second lumbar puncture was performed in that case to rule out the possibility of infection. Aseptic meningitis was diagnosed and was most likely caused by residual dimethyl sulfoxide in the culture medium owing to insufficient washing of the cells (Table 1). The adverse effects profile did not differ significantly between the MS and ALS groups. No major adverse effects were reported in any of the patients during a follow-up of up to 25 months.

Table Graphic Jump LocationTable 1. Adverse Events in Patients With MS and With ALS After MSC Transplantation
Clinical Effects

Figure 1 shows the follow-up of the mean EDSS and ALSFRS scores at baseline and at 1, 3, and 6 months after MSC transplantation. In patients with MS, the mean EDSS score declined gradually (indicating functional improvement) from 6.7 (1.0) before the treatment to 6.1 (1.2) at 1 month, 5.9 (1.4) at 3 months, and 5.9 (1.6) at 6 months after MSC injection (P < .001, P < .001, and P = .001, respectively, 2-tailed paired t test) (Figure 1A). Although the follow-up of the mean EDSS scores in the whole group is not the optimal way to assess treatment efficacy in small groups, it may provide some indication of positive effects and, most important in such a phase 1/2 study, confirm the lack of any deleterious clinical effects. More specifically, at the end of the 6 months of follow-up, the EDSS score remained unchanged in 4 patients and was reduced by 0.5 degree in 5. It improved by 1.0 degree in 1 patient, by 1.5 degrees in 3, by 2 degrees in 1, and by 2.5 degrees in 1. The EDSS score did not deteriorate in any of the patients.

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Figure 1. Clinical follow-up of patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) after transplantation of mesenchymal stem cells (MSCs). A, The Expanded Disability Status Scale (EDSS) score in patients with MS was significantly reduced at 1 (P < .001), 3 (P < .001), and 6 (P = .001) months, compared with baseline (2-tailed paired t test). B, Changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score were not statistically significant.

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In the patients with ALS, the mean ALSFRS score deteriorated slightly during the 2 months between the screening visit and the day of MSC injection but thereafter remained stable during the 6-month follow-up (20.1-20.5, with no statistically significant difference between time points) (Figure 1B).

NEURORADIOLOGICAL EFFECTS OF MSC TRANSPLANTATION

Magnetic resonance imaging (1.5 T) of the brain and whole spine during the 6-month follow-up did not reveal any significant unexpected pathology. In the MS group, no new or gadolinium-enhancing lesions were observed in the brain for up to 6 months after MSC treatment. In the 9 patients in whom the MSCs were labeled with ferumoxides, MRI of the brain and whole spine was performed at 24 to 48 hours and at 1 to 3 months after injection of MSCs. Hypointense signals in T2-weighted images, indicating the presence of ferumoxides-positive cells, were detected in the meninges of the spinal cord and nerve roots and in the spinal cord parenchyma (Figure 2). In 1 patient who received MSCs without ferumoxides labeling, a 3-T brain MRI performed 18 hours after transplantation (Figure 3) showed dependent layering of the intrathecally delivered cells in the occipital horns, suggesting dissemination of MSCs from the injection site to the ventricles of the CNS.

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Figure 2. Magnetic resonance imaging after injection of ferumoxides-labeled mesenchymal stem cells. A, An axial T2-weighted gradient echo scan through the inferior thoracic cord shows a hypointense pial signal coating the cord similar to that of superficial siderosis, characteristic of ferumoxides (Feridex)-labeled cells. B, Axial T2-weighted gradient echo scan through the cervical cord shows hypointensity of the dorsal roots and their entry zone and a similar hypointensity of the ventral root entry zones, suggesting the presence of ferumoxides-labeled cells.

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Figure 3. A 3-T diffusion-weighted axial magnetic resonance imaging scan of the brain shows hyperintense signals in the occipital horns of the brain ventricles, indicating the presence of dependent transplanted cells that were not magnetically labeled.

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IMMUNOLOGICAL EFFECTS OF MSC TRANSPLANTATION

To evaluate the in vivo immunoregulatory effects of MSC transplantation, peripheral blood monocytes were obtained from 12 patients (5 with ALS and 7 with MS), and the changes in the expression of cell surface markers and the lymphocyte proliferative responses on stimulation with phytohemagglutinin were tested before and at 4 and 24 hours after MSC administration. Analysis of the data in all 12 patients together (as a single group) using a 2-tailed paired t test showed a 72% increase in the proportion of CD4+CD25+ regulatory T cells (from 8.3% [6.4%] to 14.2% [7.5%]; P = .02) and a 30% to 60% reduction of CD86+ (from 82.6% [20.5%] to 58.8% [16.3%]; P = .02), CD83+ (from 26.6% [8.4%] to 12.3% [13.2%]; P = .02), and HLA-DR+ (from 92.1% [5.2%] to 74.6% [12.1%]; P = .004) myeloid dendritic cells and a similar reduction in the number of activated CD40+ cells (from 22.9 [5.3] to 10.7 [14.0]; P = .04) 24 hours after MSC infusion (Figure 4A and Table 2). These changes were similar in the MS and ALS groups when analyzed separately (Table 2). In addition, after stimulation of lymphocytes with the phytohemagglutinin, there was a 63% decrease in the proliferative cell response (stimulation index at baseline, 26.6 [4.1]; 24 hours later: 9.6 [4.8]; P = .001, 2-tailed paired t test) (Figure 4B). Although it is difficult to estimate the clinical relevance of these immunological effects, changes of that magnitude are stronger than those induced by the conventional immunomodulatory medications and indicate a downregulation of activated lymphocytes and antigen-presenting cells and the proliferative ability of effector cells after MSC transplantation.

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Figure 4. Immunological effects in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) injected intravenously and intrathecally with mesenchymal stem cells (MSCs). Peripheral blood monocytes were obtained from 12 patients (7 with MS and 5 with ALS, combined as a single group) at baseline and at 4 and 24 hours after autologous MSC transplantation. A, Mean (SD) changes in the proportions of CD4+CD25+ and CD40+ lymphocytes and of CD83+, CD86+, and HLA-DR+ myeloid dendritic cells (fluorescence-activated cell sorter analysis), at 4 and 24 hours after MSC transplantation. *Statistically significant changes (P < .05) compared with baseline (2-tailed paired t test). B, Changes in lymphocytic proliferation on stimulation with phytohemagglutinin after MSC transplantation (tested by means of tritiated thymidine uptake of peripheral blood lymphocytes obtained from MSC-treated patients with ALS and with MS that were then stimulated with phytohemagglutinin), at 4 and 24 hours after MSC transplantation. The differences were statistically significant (P = .001) compared with baseline (2-tailed paired t test).

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Table Graphic Jump LocationTable 2. Immunological Effects in Patients With MS and With ALS Undergoing MSC Transplantation Intravenously and Intrathecallya

Our phase 1/2 pilot clinical trial using combined intrathecal and intravenous injection of bone marrow–derived autologous MSCs in 34 patients with MS and ALS was aimed at exploring the feasibility and safety of this type of cell therapy. The 6 to 25 months of follow-up did not reveal any significant immediate or late adverse effects and indicated clinical stabilization or improvement in some patients. Magnetic resonance imaging indicated possible dissemination of the MSCs from the lumbar site of inoculation to the occipital horns, meninges, spinal roots, and spinal cord parenchyma (Figures 2 and 3). Immunological analysis of lymphocyte subsets and cytokine production, performed in 12 patients, demonstrated the immediate in vivo immunomodulating effects of MSCs, starting as early as 4 hours after MSC transplantation and including an increase in CD4+CD25+ regulatory cells and a reduction in the proportion of activated dendritic cells and lymphocytes and of lymphocyte proliferation (Figure 4).

One of the possible approaches to enhancing neuroprotective mechanisms and inducing neuroregeneration in progressive MS and ALS may involve the use of adult or nonembryonic stem cells, which are more differentiated than embryonic stem cells and can be harvested from various tissues. Bone marrow MSCs mainly support the processes of hematopoiesis and hematopoietic stem cell engraftment but can also give rise to cells of mesodermal origin such as osteoblasts, adipocytes, and chondrocytes. Recent studies have described the following additional properties of MSCs: (1) a debatable ability to transdifferentiate into cells of endodermal and ectodermal origin,6,47,48 including possible neural transdifferentiation,15,17,19 and (2) systemic (peripheral) and local (in the CNS) immunomodulatory effects.8,9,4951

The use of bone marrow–derived stem cells offers several practical advantages: (1) MSCs can be obtained readily and safely from adult bone marrow, even from patients with advanced disease; (2) MSCs, which are normally present in small concentrations in the bone marrow compartment, can be enriched and greatly expanded by in vitro culturing; (3) autologous MSCs can be administered safely without the need for immunosuppressive treatment to prevent rejection; and (4) adult MSCs were shown to be less prone to genetic abnormalities and malignant transformation during multiple passages in vitro, thus implying a low risk for induction of treatment-related malignant neoplasms.5255

The preclinical studies,2839 together with the cumulative data from ongoing clinical trials with MSCs in various clinical conditions (reviewed by Giordano et al27), provided the scientific basis for our trial. The only available data on the use of MSCs in neurological conditions include a small study56 in 7 patients with ALS and a trial from Iran57 that did not report any significant adverse events. Two additional, recently published studies, a phase 1 trial in patients with ALS (with intraspinal injection of MSCs)58 and a small pilot study with 3 patients with MS that used intravenous administration of adipose tissue MSCs,59 also support the safety of the use of MSCs.

Our main finding was the feasibility and acceptable safety profile of transplantation of autologous stem cells from the bone marrow in patients with MS and ALS. None of our patients experienced significant adverse effects during the 6- to 25-month observation. In 20 patients, follow-up MRI 1 year after transplantation did not reveal any unexpected pathology or significant new activity of the disease.

Several clinical trials in nonneurological diseases2839 have indicated that intravenous administration of MSCs is a safe procedure. Our study additionally shows an acceptable short-term safety profile of the intrathecal route of administration of stem cells at doses of up to 70 million cells per injection per patient. The intrathecal approach for cell-based therapies in neurological diseases such as MS and ALS, in which the areas of tissue damage are widespread throughout the neuroaxis, may increase the possibility of migration of the injected cells to the proximity of the CNS lesions. The injected cells may circulate with the flow of the cerebrospinal fluid and have a better chance of reaching the affected CNS areas. Our animal studies showed that this route of administration could induce superior neurotrophic and neuroprotective effects.25 However, the optimal route of stem cell administration in general—and particularly MSC administration—in patients with neurological diseases remains debatable. Other investigators have claimed that intravenous injection may be sufficient and equally effective (at least in the case of MS) because MSCs exert peripheral immunomodulating effects and may also migrate through the blood to the damaged areas of the CNS after receiving inflammatory signals.2325 A possible drawback of the intravenous administration of MSCs is that most of the cells injected into the blood will home to the lungs, lymph nodes, and other tissues, greatly reducing the number of cells available to migrate to the CNS. Moreover, intrathecal delivery of cells may focus their possible immunomodulatory and trophic effects directly on the CNS, without producing systemic adverse effects.

The initial findings of our trial support the possibility of migration of MSCs from their site of injection (lumbar area of the cerebrospinal fluid) to the brain ventricles and spinal cord parenchyma. Despite the absence of definite proof, the hypointense signals in the meninges and the spinal cord parenchyma, shown in our MRI studies (Figure 2), may indicate the presence of supraparamagnetic particles (ferumoxides-labeled MSCs) in these CNS areas. However, the hypointense areas could also be related to the presence of macrophages that phagocytized the iron oxide magnetic resonance contrast agent and migrated to the inflammatory MS lesions.

Our data also demonstrate and confirm, to our knowledge for the first time in human neurological diseases, the in vivo systemic immunomodulatory effects of MSCs previously described in animal studies.25 The finding of early clinical stabilization or improvement in some of the patients could be related to these immunomodulating effects. The possibility of neuroprotection and neuroregeneration through transdifferentiation of MSCs into cells of the neuronal or glial lineage, although theoretically viable, has yet to be proved by neuroimaging studies. Further controlled trials are warranted to evaluate the long-term safety and the potential clinical efficacy of MSC transplantation. According to recent consensus papers,60,61 intravenous injection of MSCs (at a suggested dose of 106/kg, which has been shown to be optimal for effective immunomodulation) seems to be the most feasible approach in designing future efficacy trials in patients with active MS.

Correspondence: Dimitrios Karussis, MD, PhD, Agnes Ginges Center for Neurogenetics and Multiple Sclerosis Center and Department of Neurology, Hadassah-Hebrew University Hospital, Ein Karem, Jerusalem IL-91120, Israel (karus@cc.huji.ac.il).

Accepted for Publication: May 25, 2010.

Author Contributions:Study concept and design: Karussis, Vaknin-Dembinsky, Gomori, Bulte, Petrou, Ben-Hur, Abramsky, and Slavin. Acquisition of data: Karussis, Karageorgiou, Vaknin-Dembinsky, Gowda-Kurkalli, Gomori, Kassis, Petrou, Ben-Hur, Abramsky, and Slavin. Analysis and interpretation of data: Karussis, Vaknin-Dembinsky, Gomori, Kassis, Bulte, Petrou, Ben-Hur, Abramsky, and Slavin. Drafting of the manuscript: Karussis, Karageorgiou, Vaknin-Dembinsky, Gowda-Kurkalli, Gomori, Kassis, Bulte, Petrou, Ben-Hur, Abramsky, and Slavin. Critical revision of the manuscript for important intellectual content: Karussis, Vaknin-Dembinsky, Gomori, Bulte, Petrou, Ben-Hur, Abramsky, and Slavin. Statistical analysis: Karussis and Kassis. Obtained funding: Karussis and Bulte. Administrative, technical, and material support: Karussis, Karageorgiou, Vaknin-Dembinsky, Gowda-Kurkalli, Gomori, Kassis, Bulte, Petrou, Ben-Hur, Abramsky, and Slavin. Study supervision: Karussis, Gowda-Kurkalli, Gomori, Petrou, and Slavin.

Financial Disclosure: None reported.

Funding/Support: This work was supported by the ECTRIMS Fellowship grant 2009-2010. Part of this study was funded by NMSS RG3630 and TEDCO MD Stem Cell Fund ESC 06-29-01.

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Meisel  RZibert  ALaryea  MGöbel  UDäubener  WDilloo  D Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004;103 (12) 4619- 4621
PubMed Link to Article
Glennie  SSoeiro  IDyson  PJLam  EWDazzi  F Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005;105 (7) 2821- 2827
PubMed Link to Article
Di Nicola  MCarlo-Stella  CMagni  M  et al.  Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99 (10) 3838- 3843
PubMed Link to Article
Deng  WHan  QLiao  LYou  SDeng  HZhao  RC Effects of allogeneic bone marrow–derived mesenchymal stem cells on T and B lymphocytes from BXSB mice. DNA Cell Biol 2005;24 (7) 458- 463
PubMed Link to Article
Woodbury  DSchwarz  EJProckop  DJBlack  IB Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000;61 (4) 364- 370
PubMed Link to Article
Song  LTuan  RS Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow. FASEB J 2004;18 (9) 980- 982
PubMed
Sanchez-Ramos  JSong  SCardozo-Pelaez  F  et al.  Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000;164 (2) 247- 256
PubMed Link to Article
Lu  PBlesch  ATuszynski  MH Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? J Neurosci Res 2004;77 (2) 174- 191
PubMed Link to Article
Bossolasco  PCova  LCalzarossa  C  et al.  Neuro-glial differentiation of human bone marrow stem cells in vitro. Exp Neurol 2005;193 (2) 312- 325
PubMed Link to Article
Akiyama  YRadtke  CHonmou  OKocsis  JD Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia 2002;39 (3) 229- 236
PubMed Link to Article
Inoue  MHonmou  OOka  SHoukin  KHashi  KKocsis  JD Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord. Glia 2003;44 (2) 111- 118
PubMed Link to Article
Zappia  ECasazza  SPedemonte  E  et al.  Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005;106 (5) 1755- 1761
PubMed Link to Article
Zhang  JLi  YChen  J  et al.  Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 2005;195 (1) 16- 26
PubMed Link to Article
Zhang  JLi  YLu  M  et al.  Bone marrow stromal cells reduce axonal loss in experimental autoimmune encephalomyelitis mice. J Neurosci Res 2006;84 (3) 587- 595
PubMed Link to Article
Kassis  IGrigoriadis  NGowda-Kurkalli  B  et al.  Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol 2008;65 (6) 753- 761
PubMed Link to Article
Chen  JLi  YWang  LLu  MZhang  XChopp  M Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 2001;189 (1-2) 49- 57
PubMed Link to Article
Giordano  AGalderisi  UMarino  IR From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol 2007;211 (1) 27- 35
PubMed Link to Article
Horwitz  EMProckop  DJFitzpatrick  LA  et al.  Transplantability and therapeutic effects of bone marrow–derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999;5 (3) 309- 313
PubMed Link to Article
Horwitz  EMProckop  DJGordon  PL  et al.  Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 2001;97 (5) 1227- 1231
PubMed Link to Article
Wollert  KCMeyer  GPLotz  J  et al.  Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364 (9429) 141- 148
PubMed Link to Article
Stamm  CWestphal  BKleine  HD  et al.  Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003;361 (9351) 45- 46
PubMed Link to Article
Perin  ECDohmann  HFBorojevic  R  et al.  Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003;107 (18) 2294- 2302
PubMed Link to Article
Perin  ECDohmann  HFBorojevic  R  et al.  Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation 2004;110 (11) ((suppl 1)) II213- II218
PubMed Link to Article
Koç  ONDay  JNieder  MGerson  SLLazarus  HMKrivit  W Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002;30 (4) 215- 222
PubMed Link to Article
Assmus  BSchächinger  VTeupe  C  et al.  Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002;106 (24) 3009- 3017
PubMed Link to Article
Chen  SLFang  WWYe  F  et al.  Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004;94 (1) 92- 95
PubMed Link to Article
Ferrari  GCusella-De Angelis  GColetta  M  et al.  Muscle regeneration by bone marrow–derived myogenic progenitors [published correction appears in Science. 1998;281(5379):923]. Science 1998;279 (5356) 1528- 1530
PubMed Link to Article
Katritsis  DGSotiropoulou  PAKarvouni  E  et al.  Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheter Cardiovasc Interv 2005;65 (3) 321- 329
PubMed Link to Article
Koç  ONGerson  SLCooper  BW  et al.  Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 2000;18 (2) 307- 316
PubMed
Bulte  JWKraitchman  DL Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 2004;17 (7) 484- 499
PubMed Link to Article
de Vries  IJLesterhuis  WJBarentsz  JO  et al.  Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol 2005;23 (11) 1407- 1413
PubMed Link to Article
Toso  CVallee  JPMorel  P  et al.  Clinical magnetic resonance imaging of pancreatic islet grafts after iron nanoparticle labeling. Am J Transplant 2008;8 (3) 701- 706
PubMed Link to Article
Zhu  JWu  XZhang  HL Adult neural stem cell therapy: expansion in vitro, tracking in vivo and clinical transplantation. Curr Drug Targets 2005;6 (1) 97- 110
PubMed Link to Article
Poser  CMPaty  DWScheinberg  L  et al.  New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13 (3) 227- 231
PubMed Link to Article
Brooks  BRSubcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases; El Escorial “Clinical Limits of Amyotrophic Lateral Sclerosis” Workshop Contributors, El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1994;124 ((suppl)) 96- 107
PubMed Link to Article
Bulte  JWArbab  ASDouglas  TFrank  JA Preparation of magnetically labeled cells for cell tracking by magnetic resonance imaging. Methods Enzymol 2004;386275- 299
PubMed
Oswald  JBoxberger  SJørgensen  B  et al.  Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 2004;22 (3) 377- 384
PubMed Link to Article
Taléns-Visconti  RBonora  AJover  R  et al.  Hepatogenic differentiation of human mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells. World J Gastroenterol 2006;12 (36) 5834- 5845
PubMed
Krampera  MGlennie  SDyson  J  et al.  Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003;101 (9) 3722- 3729
PubMed Link to Article
Le Blanc  KTammik  CRosendahl  KZetterberg  ERingdén  O HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003;31 (10) 890- 896
PubMed Link to Article
Uccelli  AZappia  EBenvenuto  FFrassoni  FMancardi  G Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection. Expert Opin Biol Ther 2006;6 (1) 17- 22
PubMed Link to Article
Izadpanah  RTrygg  CPatel  B  et al.  Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem 2006;99 (5) 1285- 1297
PubMed Link to Article
Draper  JSMoore  HDRuban  LNGokhale  PJAndrews  PW Culture and characterization of human embryonic stem cells. Stem Cells Dev 2004;13 (4) 325- 336
PubMed Link to Article
Lee  KMajumdar  MKBuyaner  DHendricks  JKPittenger  MFMosca  JD Human mesenchymal stem cells maintain transgene expression during expansion and differentiation. Mol Ther 2001;3 (6) 857- 866
PubMed Link to Article
Asano  TSasaki  KKitano  YTerao  KHanazono  Y In vivo tumor formation from primate embryonic stem cells. Methods Mol Biol 2006;329459- 467
PubMed
Mazzini  LMareschi  KFerrero  I  et al.  Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis. Neurol Res 2006;28 (5) 523- 526
PubMed Link to Article
Mohyeddin Bonab  MYazdanbakhsh  SLotfi  J  et al.  Does mesenchymal stem cell therapy help multiple sclerosis patients? report of a pilot study. Iran J Immunol 2007;4 (1) 50- 57
PubMed
Mazzini  LFerrero  ILuparello  V  et al.  Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a phase I clinical trial. Exp Neurol 2010;223 (1) 229- 237
PubMed Link to Article
Riordan  NHIchim  TEMin  WP  et al.  Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med April2009;729
PubMed Link to Article
Martino  GFranklin  RJVan Evercooren  ABKerr  DAStem Cells in Multiple Sclerosis (STEMS) Consensus Group, Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol 2010;6 (5) 247- 255
PubMed Link to Article
Freedman  MSBar-Or  AAtkins  HL  et al. MSCT Study Group, The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler 2010;16 (4) 503- 510
PubMed Link to Article

Figures

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Figure 1. Clinical follow-up of patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) after transplantation of mesenchymal stem cells (MSCs). A, The Expanded Disability Status Scale (EDSS) score in patients with MS was significantly reduced at 1 (P < .001), 3 (P < .001), and 6 (P = .001) months, compared with baseline (2-tailed paired t test). B, Changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score were not statistically significant.

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Figure 2. Magnetic resonance imaging after injection of ferumoxides-labeled mesenchymal stem cells. A, An axial T2-weighted gradient echo scan through the inferior thoracic cord shows a hypointense pial signal coating the cord similar to that of superficial siderosis, characteristic of ferumoxides (Feridex)-labeled cells. B, Axial T2-weighted gradient echo scan through the cervical cord shows hypointensity of the dorsal roots and their entry zone and a similar hypointensity of the ventral root entry zones, suggesting the presence of ferumoxides-labeled cells.

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Figure 3. A 3-T diffusion-weighted axial magnetic resonance imaging scan of the brain shows hyperintense signals in the occipital horns of the brain ventricles, indicating the presence of dependent transplanted cells that were not magnetically labeled.

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Place holder to copy figure label and caption

Figure 4. Immunological effects in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) injected intravenously and intrathecally with mesenchymal stem cells (MSCs). Peripheral blood monocytes were obtained from 12 patients (7 with MS and 5 with ALS, combined as a single group) at baseline and at 4 and 24 hours after autologous MSC transplantation. A, Mean (SD) changes in the proportions of CD4+CD25+ and CD40+ lymphocytes and of CD83+, CD86+, and HLA-DR+ myeloid dendritic cells (fluorescence-activated cell sorter analysis), at 4 and 24 hours after MSC transplantation. *Statistically significant changes (P < .05) compared with baseline (2-tailed paired t test). B, Changes in lymphocytic proliferation on stimulation with phytohemagglutinin after MSC transplantation (tested by means of tritiated thymidine uptake of peripheral blood lymphocytes obtained from MSC-treated patients with ALS and with MS that were then stimulated with phytohemagglutinin), at 4 and 24 hours after MSC transplantation. The differences were statistically significant (P = .001) compared with baseline (2-tailed paired t test).

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Tables

Table Graphic Jump LocationTable 1. Adverse Events in Patients With MS and With ALS After MSC Transplantation
Table Graphic Jump LocationTable 2. Immunological Effects in Patients With MS and With ALS Undergoing MSC Transplantation Intravenously and Intrathecallya

References

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Spaggiari  GMCapobianco  ABecchetti  SMingari  MCMoretta  L Mesenchymal stem cell–natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2–induced NK-cell proliferation. Blood 2006;107 (4) 1484- 1490
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PubMed Link to Article
Meisel  RZibert  ALaryea  MGöbel  UDäubener  WDilloo  D Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004;103 (12) 4619- 4621
PubMed Link to Article
Glennie  SSoeiro  IDyson  PJLam  EWDazzi  F Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005;105 (7) 2821- 2827
PubMed Link to Article
Di Nicola  MCarlo-Stella  CMagni  M  et al.  Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99 (10) 3838- 3843
PubMed Link to Article
Deng  WHan  QLiao  LYou  SDeng  HZhao  RC Effects of allogeneic bone marrow–derived mesenchymal stem cells on T and B lymphocytes from BXSB mice. DNA Cell Biol 2005;24 (7) 458- 463
PubMed Link to Article
Woodbury  DSchwarz  EJProckop  DJBlack  IB Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000;61 (4) 364- 370
PubMed Link to Article
Song  LTuan  RS Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow. FASEB J 2004;18 (9) 980- 982
PubMed
Sanchez-Ramos  JSong  SCardozo-Pelaez  F  et al.  Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000;164 (2) 247- 256
PubMed Link to Article
Lu  PBlesch  ATuszynski  MH Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? J Neurosci Res 2004;77 (2) 174- 191
PubMed Link to Article
Bossolasco  PCova  LCalzarossa  C  et al.  Neuro-glial differentiation of human bone marrow stem cells in vitro. Exp Neurol 2005;193 (2) 312- 325
PubMed Link to Article
Akiyama  YRadtke  CHonmou  OKocsis  JD Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia 2002;39 (3) 229- 236
PubMed Link to Article
Inoue  MHonmou  OOka  SHoukin  KHashi  KKocsis  JD Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord. Glia 2003;44 (2) 111- 118
PubMed Link to Article
Zappia  ECasazza  SPedemonte  E  et al.  Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005;106 (5) 1755- 1761
PubMed Link to Article
Zhang  JLi  YChen  J  et al.  Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 2005;195 (1) 16- 26
PubMed Link to Article
Zhang  JLi  YLu  M  et al.  Bone marrow stromal cells reduce axonal loss in experimental autoimmune encephalomyelitis mice. J Neurosci Res 2006;84 (3) 587- 595
PubMed Link to Article
Kassis  IGrigoriadis  NGowda-Kurkalli  B  et al.  Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol 2008;65 (6) 753- 761
PubMed Link to Article
Chen  JLi  YWang  LLu  MZhang  XChopp  M Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 2001;189 (1-2) 49- 57
PubMed Link to Article
Giordano  AGalderisi  UMarino  IR From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol 2007;211 (1) 27- 35
PubMed Link to Article
Horwitz  EMProckop  DJFitzpatrick  LA  et al.  Transplantability and therapeutic effects of bone marrow–derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999;5 (3) 309- 313
PubMed Link to Article
Horwitz  EMProckop  DJGordon  PL  et al.  Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 2001;97 (5) 1227- 1231
PubMed Link to Article
Wollert  KCMeyer  GPLotz  J  et al.  Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364 (9429) 141- 148
PubMed Link to Article
Stamm  CWestphal  BKleine  HD  et al.  Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003;361 (9351) 45- 46
PubMed Link to Article
Perin  ECDohmann  HFBorojevic  R  et al.  Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003;107 (18) 2294- 2302
PubMed Link to Article
Perin  ECDohmann  HFBorojevic  R  et al.  Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation 2004;110 (11) ((suppl 1)) II213- II218
PubMed Link to Article
Koç  ONDay  JNieder  MGerson  SLLazarus  HMKrivit  W Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002;30 (4) 215- 222
PubMed Link to Article
Assmus  BSchächinger  VTeupe  C  et al.  Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002;106 (24) 3009- 3017
PubMed Link to Article
Chen  SLFang  WWYe  F  et al.  Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004;94 (1) 92- 95
PubMed Link to Article
Ferrari  GCusella-De Angelis  GColetta  M  et al.  Muscle regeneration by bone marrow–derived myogenic progenitors [published correction appears in Science. 1998;281(5379):923]. Science 1998;279 (5356) 1528- 1530
PubMed Link to Article
Katritsis  DGSotiropoulou  PAKarvouni  E  et al.  Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheter Cardiovasc Interv 2005;65 (3) 321- 329
PubMed Link to Article
Koç  ONGerson  SLCooper  BW  et al.  Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 2000;18 (2) 307- 316
PubMed
Bulte  JWKraitchman  DL Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 2004;17 (7) 484- 499
PubMed Link to Article
de Vries  IJLesterhuis  WJBarentsz  JO  et al.  Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol 2005;23 (11) 1407- 1413
PubMed Link to Article
Toso  CVallee  JPMorel  P  et al.  Clinical magnetic resonance imaging of pancreatic islet grafts after iron nanoparticle labeling. Am J Transplant 2008;8 (3) 701- 706
PubMed Link to Article
Zhu  JWu  XZhang  HL Adult neural stem cell therapy: expansion in vitro, tracking in vivo and clinical transplantation. Curr Drug Targets 2005;6 (1) 97- 110
PubMed Link to Article
Poser  CMPaty  DWScheinberg  L  et al.  New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13 (3) 227- 231
PubMed Link to Article
Brooks  BRSubcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases; El Escorial “Clinical Limits of Amyotrophic Lateral Sclerosis” Workshop Contributors, El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1994;124 ((suppl)) 96- 107
PubMed Link to Article
Bulte  JWArbab  ASDouglas  TFrank  JA Preparation of magnetically labeled cells for cell tracking by magnetic resonance imaging. Methods Enzymol 2004;386275- 299
PubMed
Oswald  JBoxberger  SJørgensen  B  et al.  Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 2004;22 (3) 377- 384
PubMed Link to Article
Taléns-Visconti  RBonora  AJover  R  et al.  Hepatogenic differentiation of human mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells. World J Gastroenterol 2006;12 (36) 5834- 5845
PubMed
Krampera  MGlennie  SDyson  J  et al.  Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003;101 (9) 3722- 3729
PubMed Link to Article
Le Blanc  KTammik  CRosendahl  KZetterberg  ERingdén  O HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003;31 (10) 890- 896
PubMed Link to Article
Uccelli  AZappia  EBenvenuto  FFrassoni  FMancardi  G Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection. Expert Opin Biol Ther 2006;6 (1) 17- 22
PubMed Link to Article
Izadpanah  RTrygg  CPatel  B  et al.  Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem 2006;99 (5) 1285- 1297
PubMed Link to Article
Draper  JSMoore  HDRuban  LNGokhale  PJAndrews  PW Culture and characterization of human embryonic stem cells. Stem Cells Dev 2004;13 (4) 325- 336
PubMed Link to Article
Lee  KMajumdar  MKBuyaner  DHendricks  JKPittenger  MFMosca  JD Human mesenchymal stem cells maintain transgene expression during expansion and differentiation. Mol Ther 2001;3 (6) 857- 866
PubMed Link to Article
Asano  TSasaki  KKitano  YTerao  KHanazono  Y In vivo tumor formation from primate embryonic stem cells. Methods Mol Biol 2006;329459- 467
PubMed
Mazzini  LMareschi  KFerrero  I  et al.  Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis. Neurol Res 2006;28 (5) 523- 526
PubMed Link to Article
Mohyeddin Bonab  MYazdanbakhsh  SLotfi  J  et al.  Does mesenchymal stem cell therapy help multiple sclerosis patients? report of a pilot study. Iran J Immunol 2007;4 (1) 50- 57
PubMed
Mazzini  LFerrero  ILuparello  V  et al.  Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a phase I clinical trial. Exp Neurol 2010;223 (1) 229- 237
PubMed Link to Article
Riordan  NHIchim  TEMin  WP  et al.  Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med April2009;729
PubMed Link to Article
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