Therapeutic Use of Intrathecal Mesenchymal Stem Cells in patients with Multiple Sclerosis: A Pilot Study with Booster Injection.

BACKGROUND: Mesenchymal stem cells (MSCs) are a potential therapy for various diseases. Here, the results of intrathecal injection of MSCs in multiple sclerosis (MS) patients are reported. MATERIALS AND METHODS: Four patients were enrolled in the study. Three were male and one was female. There were three secondary-progressive MS patients and one relapsing-remitting MS patient. An amount of 50-80 ml of bone marrow was collected from the patients. MSC cultures were collected for each microbiological examination at each change of medium and passage as well as at the time of sample injection. Then, MSCs were injected into the patients by the intrathecal method. In two patients, the injection was replicated in 1 year. RESULTS: All the patients were followed up for 2 years. Three patients who had secondary progression did not show disease progress after the injection, and the disease entered a stable state. A degree of recovery was observed in two patients. The relapsing-remitting patient suffered an attack that led to corticosteroid injection. None of the patients reported side effects. In terms of magnetic resonance imaging, there were no new plaques or enhanced plaques. CONCLUSION: This study suggests that injection of MSC can be a suitable method, especially for secondary-progressive patients. It seems that reinjection of these stem cells can be safe and sustaining it positively increases the effects of this therapeutic approach.

Evaluation of cytokines in multiple sclerosis patients treated with mesenchymal stem cells.

BACKGROUND AND AIMS: Mesenchymal stem cells (MSC) are currently strong candidates for stem cell therapy. Cytokines have a profound effect on the resultant immune responses. This study aims to evaluate variations in the cytokine profile of multiple sclerosis patients treated with autologous MSC. METHODS: Twenty five patients received one dose of intrathecal MSCs (mean number: 29.5 × 106). To measure the gene expression of FOXP3, IFN-γ, TGF-ß, IL-4, IL-10, IL-6, and their serum proteins, samples were collected at five intervals: day 0 prior to injection and months 1, 3, 6, and 12 after MSC therapy. Gene expression was evaluated via real-time PCR and protein values were measured by ELISA. RESULTS: There were no statistically significant variations in gene expression and serum level of cytokines after a 1-year follow-up of MSC-treated MS patients. The only correlation found was an increase in IL-6 gene expression in patients with progressive disease. CONCLUSION: Intrathecal injection of MSCs does not affect cytokine variation in peripheral blood. Because the condition of most of our patients either improved or stabilized after stem cell therapy (SCT), we speculate that the immunomodulatory or neuroregenerative effects of MSC are exerted locally in the central nervous system.

Immunomodulatory effects of human umbilical cord Wharton's jelly-derived mesenchymal stem cells on differentiation, maturation and endocytosis of monocyte-derived dendritic cells.

The Wharton's jelly of the umbilical cord is believed to be a source of mesenchymal stem cells (MSCs) which can be therapeutically applied in degenerative diseases.In this study, we investigated the immunomodulatory effect of umbilical cord derived-mesenchymal stem cells (UC-MSCs) and bone marrow-derived-mesenchymal stem cells (BM-MSCs) on differentiation, maturation, and endocytosis of monocyte-derived dendritic cells in a transwell culture system under laboratory conditions. Monocytes were differentiated into immature dendritic cells (iDCs) in the presence of GM-CSF and IL-4 for 6 days and then differentiated into mature dendritic cells (mDCs) in the presence of TNF-α for 2 days. In every stage of differentiation, immature and mature dendritic cells were separately co-cultured with UC-MSCs and BM-MSCs. The findings showed that UC-MSCs and BM-MSCs inhibited strongly differentiation and maturation of dendritic cells at higher dilution ratios (1:1). The BM-MSCs and UC-MSCs showed more inhibitory effect on CD1a, CD83, CD86 expression, and dendritic cell endocytic activity, respectively. On the other hand, these cells severely up-regulated CD14 marker expression. We concluded that UC-MSCs and BM-MSCs could inhibit differentiation, maturation and endocytosis in monocyte-derived DCs through the secreted factors and free of any cell-cell contacts under laboratory conditions. As DCs are believed to be the main antigen presenting cells for naïve T cells in triggering immune responses, it would be logical that their inhibitory effect on differentiation, maturation and function can decrease or modulate immune and inflammatory responses.

FOXP3 gene expression in multiple sclerosis patients pre- and post mesenchymal stem cell therapy.

Multiple Sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS), which mainly affects young adults. Activated T lymphocytes promote the neuro-inflammatory cascade of MS by secreting pro-inflammatory cytokines and play a significant role in its pathogenesis. T lymphocytes may trigger the inflammation, which in turn leads to axonal loss and neurodegeneration observed in the course of MS. Currently, there is no cure for MS, however, one of the most promising neuroprotective research tools consists of the use of bone marrow derived mesenchymal stem cells (MSC). This method promotes immune system regulation and possibly induces neurological repair and re-myelination of the damaged axons. Recent studies have shown that MSC exert an immune regulatory function and induce T regulatory-cell proliferation, therefore, it may serve as a potentially useful treatment for immune-mediated diseases such as MS. In this pilot study a group of MS patients underwent MSC therapy and we assayed the expression of an X-linked transcription factor, FoxP3, as a specific marker of T Regulatory cells in peripheral blood, prior to and after the treatment. Using q RT-PCR for measurement of expression of FoxP3 by peripheral blood mononuclear cells, we found that in all subjects, except for one, the expression of FoxP3 at 6 months after intrathecal injection of MSC was significantly higher than the levels prior to treatment. Such significant enhanced expression of FoxP3 associated with clinical stability. Findings from this pilot study further support the potential of bone marrow derived MSC for treatment of MS patients.

Intracoronary administration of autologous mesenchymal stem cells in a critically ill patient with dilated cardiomyopathy.

Relatively high prevalence of dilated cardiomyopathy in children, unfavorable response to traditional drug therapy, and limitations in heart transplantation call for new therapeutic options. Stem cell therapy can be promising in children suffering from this disease. The presented case documents that intracoronary injection of autologous bone marrow-derived mesenchymal stem cells in a boy with progressive dilated cardiomyopathy is feasible and safe. Furthermore, it may positively influence functional class, quality of life, and echocardiographic indices of cardiac function.

Autologous in vitro expanded mesenchymal stem cell therapy for human old myocardial infarction.

BACKGROUND: Stem cell transplantation after myocardial infarction has been claimed to restore cardiac function. Mesenchymal stem cells attract a lot of attention because of the feasibility of in vivo and ex vivo differentiation to cardiomyocytes and endothelial cells as well as their trophic effect on tissue repair. In this study, we investigated the efficacy of autologous bone marrow derived mesenchymal stem cells in improving heart function in patients with old myocardial infarction. METHODS: Eight patients with old myocardial infarction and proper inclusion criteria were injected with mesenchymal stem cells at the time of coronary artery bypass grafting or percutaneous coronary intervention (test group) and compared with eight matched patients who received the same treatment without mesenchymal stem cell injection (control group). Evaluation of heart function was done by echocardiography plus single-photon emission computed tomography before and six months after the procedure. Serial clinical examination was performed every month through New York Heart Association class. RESULTS: The mean New York Heart Association class and single-photon emission computed tomography scan results decreased significantly in the test group (P=0.000 and 0.002, respectively) and in the control group (P=0.049 and 0.007, respectively) after the procedure at six months follow-up. Left ventricular ejection fraction increased significantly in the test group (P= 0.005) but not in the control group. In comparison between the test and control groups the results of New York Heart Association class assessment and single-photon emission computed tomography demonstrated significant improvement in the test group (P=0.005 and 0.013, respectively). There were no significant differences between the baseline variables in the two groups. CONCLUSION: Transplantation of ex vivo expanded bone marrow derived mesenchymal stem cell in patients with old myocardial infarction is a safe and feasible procedure. These cells improve the cardiac function without serious adverse effects.

Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis.

BACKGROUND: The standard treatment for decompensated liver cirrhosis is liver transplantation. However, it has several limitations. Recent animal studies suggest that bone marrow stem cell transplantation can lead to regression of liver fibrosis. The objective of this study was to determine the safety and feasibility of autologous bone marrow-mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis. METHODS: In this phase 1 trial, four patients with decompensated liver cirrhosis were included. Their bone marrow was aspirated, mesenchymal stem cells were cultured, and a mean 31.73 x 10(6) mesenchymal stem cells were infused through a peripheral vein. Primary outcomes were evaluating the safety and feasibility of the work. Secondary outcomes were evaluating changes in the model for end-stage liver disease score, and the quality of life of the patients. RESULTS: There were no side-effects in the patients during follow-up. The model for end-stage liver disease scores of patients 1, and 4 improved by four and three points, respectively by the end of follow-up. Furthermore, the quality of life of all four patients improved by the end of follow-up. Using SF-36 questionnaire, the mean physical component scale increased from 31.44 to 65.19, and the mean mental component scale increased from 36.32 to 65.55. CONCLUSION: Mesenchymal stem cell transplantation seems to be feasible and safe in the treatment of decompensated liver cirrhosis.

Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study.

BACKGROUND: Mesenchymal stem cells (MSCs) with their potential to differentiate into mesodermal and non-mesodermal lineages have several immunomodulatory characteristics. These properties make them promising tools in cell and gene therapy. OBJECTIVE: To evaluate the potential therapeutic applications of autologous MSC in improving clinical manifestations of MS patients. METHODS: Ten patients were included in this pilot study. All had progressive disease that had not responded to disease modifying agents including Mitoxantrone. Their Expanded Disability Status Scale (EDSS) score ranged from 3.5 to 6. Patients were injected intrathecally with culture expanded MSCs. They were followed with monthly neurological assessment and a MRI scan at the end of the first year. RESULTS: During 13 to 26 months of follow up (mean: 19 months), the EDSS of one patient improved from 5 to 2.5 score. Four patients showed no change in EDSS. Five patients' EDSS increased from 0.5 to 2.5. In the functional system assessment, six patients showed some degree of improvement in their sensory, pyramidal, and cerebellar functions. One showed no difference in clinical assessment and three deteriorated. The result of MRI assessment after 12 months was as following: seven patients with no difference, two showed an extra plaque, and one patient showed decrease in the number of plaques. CONCLUSION: This preliminary report emphasizes on the feasibility of autologous MSC for treatment of MS patients. However, in order to draw a definitive conclusion a larger sample size is required.