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Seoul, South Korea

Kim H.Y.,Hanyang University | Moon C.,Hanyang University | Kim K.S.,CoreStem Inc. | Oh K.W.,Hanyang University | And 3 more authors.
Journal of Clinical Neurology (Korea)

Background and Purpose: It has been shown that erythropoietin is neuroprotective in animal models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The aim of this study was to determine the safety and feasibility of repetitive high-dose recombinant human erythropoietin (rhEPO) therapy in ALS patients.Methods: Two consecutive studies were conducted. We frst recruited 26 subjects for an initial single-arm safety study. After a lead-in period of 3 months to assess the disease progression, rhE-PO was infused intravenously (35,000 IU) once per month for 3 months, and the subjects were followed for an additional 3 months. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used for clinical assessment. After confrming the safety of rhEPO, 60 subjects were recruited for the second controlled study (rhEPO and control groups), which involved a total of 6 infusions at a rate of 1/month.Results: There were no serious adverse events in the first study. The mean rate of decline in the ALSFRS-R score was lower during the treatment period than during the lead-in period (mean± SD: 2.6±1.8 and 3.7±2.6, respectively; p=0.02). However, the rate of decline during the subsequent 3 months returned to that observed in the lead-in period. In the second study, the mean rate of decline in ALSFRS-R score was significantly lower in the rhEPO group than in the control group (during months 0–3, 1.8±1.7 vs. 3.1±2.3, p=0.03; during months 4–6, 2.1±2.2 vs. 3.5±2.3, p=0.02).Conclusions: Intravenous high-dose rhEPO is both safe and feasible for the treatment of ALS. Further investigation using different intervals and doses should be considered. © 2014 Korean Neurological Association. Source

Kim H.Y.,Hanyang University | Kim H.,Laboratory Animal Center | Oh K.-W.,Hanyang University | Oh S.-I.,Hanyang University | And 5 more authors.
Stem Cells

Bone marrow mesenchymal stromal cells (MSCs) can modify disease progression in amyotrophic lateral sclerosis (ALS) model. However, there are currently no accurate biological markers for predicting the efficacy of autologous MSC transplants in ALS patients. This open-label, singlearm, investigator-initiated clinical study was designed to identify markers of MSCs that could be used as potential predictors of response to autologous MSC therapy in patients with ALS. We enrolled 37 patients with ALS who received autologous MSCs via intrathecal injection in two monthly doses. After a 6-month follow-up period, the patients were categorized as responders and non-responders based on their scores on the revised ALS Functional Rating Scale (ALSFRSR). Biological markers including β-fibroblast growth factor-2, stromal cell-derived factor-1α, vascular endothelial growth factor (VEGF), insulin-like growth factor-1, brain-derived neurotrophic factor, angiogenin (ANG), interleukin (IL)24, IL-10, and transforming growth factor-β (TGF-β) were measured in the MSC cultures and their levels were compared between the responders and nonresponders. To confirm the markers' predictive ability, MSCs isolated from one patient in each group were transplanted into the cisterna magna of mutant SOD1G93A transgenic mice to measure their lifespans, locomotor activity, and motor neuron numbers. The levels of VEGF, ANG, and TGF-β were significantly higher in responders than in nonresponders. In the mouse model, the recipients of responder MSCs had a significantly slower onset of symptoms and a significantly longer lifespan than the recipients of nonresponders or controls. Our data suggest that VEGF, ANG, and TGF-β levels in MSCs could be used as potential biological markers to predict the effectiveness of autologous MSC therapy and to identify those patients who could optimally benefit from MSC treatment. © 2014 AlphaMed Press. Source

Kwon M.-S.,Korea University | Noh M.-Y.,Hanyang University | Oh K.-W.,Hanyang University | Cho K.-A.,Hanyang University | And 4 more authors.
Journal of Neurochemistry

In a previous study, we reported that intrathecal injection of mesenchymal stem cells (MSCs) slowed disease progression in G93A mutant superoxide dismutase1 transgenic mice. In this study, we found that intrathecal MSC administration vastly increased the infiltration of peripheral immune cells into the spinal cord of Amyotrophic lateral sclerosis (ALS) mice (G93A mutant superoxide dismutase1 transgenic). Thus, we investigated the immunomodulatory effect of MSCs on peripheral blood mononuclear cells (PBMCs) in ALS patients, focusing on regulatory T lymphocytes (Treg; CD4+/CD25high/FoxP3+) and the mRNA expression of several cytokines (IFN-c, TNF-a, IL-17, IL-4, IL-10, IL-13, and TGF-b). Peripheral blood samples were obtained from nine healthy controls (HC) and sixteen patients who were diagnosed with definite or probable ALS. Isolated PBMCs from the blood samples of all subjects were co-cultured with MSCs for 24 or 72 h. Based on a fluorescence- activated cell sorting analysis, we found that co-culture with MSCs increased the Treg/total T-lymphocyte ratio in the PBMCs from both groups according to the co-culture duration. Co-culture of PBMCs with MSCs for 24 h led to elevated mRNA levels of IFN-c and IL-10 in the PBMCs from both groups. However, after co-culturing for 72 h, although the IFNc mRNA level had returned to the basal level in co-cultured HC PBMCs, the IFN-c mRNA level in co-cultured ALS PBMCs remained elevated. Additionally, the levels of IL-4 and TGF-b were markedly elevated, along with Gata3 mRNA, a Th2 transcription factor mRNA, in both HC and ALS PBMCs cocultured for 72 h. The elevated expression of these cytokines in the co-culture supernatant was confirmed via ELISA. Furthermore, we found that the increased mRNA level of indoleamine 2,3-dioxygenase (IDO) in the co-cultured MSCs was correlated with the increase in Treg induction. These findings of Treg induction and increased anti-inflammatory cytokine expression in co-cultured ALS PBMCs provide indirect evidence that MSCs may play a role in the immunomodulation of inflammatory responses when MSC therapy is targeted to ALS patients. © 2014 International Society for Neurochemistry. Source

Jang E.,Hanyang University | Jeong M.,Hanyang University | Kim S.,Hanyang University | Jang K.,Hanyang University | And 5 more authors.
Cell Transplantation

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to components of the cell nucleus. These autoantibodies are predominantly produced with the help of follicular helper T (Tfh) cells and form immune complexes that trigger widespread inflammatory damage, including nephritis. In recent studies, mesenchymal stem cells (MSCs) elicited diverse, even opposing, effects in experimental and clinical SLE. Here we investigated the effect of human bone marrow-derived MSCs (hBMMSCs) in a murine model of SLE, the F1 hybrid between New Zealand Black and New Zealand White strains (NZB/W). We found that infusion of female NZB/W mice with hBM-MSCs attenuated glomerulonephritis; it also decreased levels of autoantibodies and the incidence of proteinuria and improved survival. These effects coincided with a decrease in Tfh cells and downstream components. Infiltration of long-lived plasma cells into the inflamed kidney was also reduced in the hBM-MSC-treated mice. Importantly, hBM-MSCs directly suppressed the in vitro differentiation of naive CD4+ T cells toward Tfh cells in a contact-dependent manner. These results suggest that MSCs attenuate lupus nephritis by suppressing the development of Tfh cells and the subsequent activation of humoral immune components. They thus reveal a novel mechanism by which MSCs regulate humoral autoimmune diseases such as SLE. © 2016 Cognizant, LLC. Source

Cho G.-W.,Hanyang University | Noh M.-Y.,Hanyang University | Kim H.Y.,Hanyang University | Koh S.-H.,Hanyang University | And 2 more authors.
Stem Cells and Development

Human bone marrow stromal cells (BM-SCs) possess the potential to differentiate, self-renew, and produce diverse trophic/growth factors and are an excellent cell therapy tool for degenerative diseases. However, they exhibit different therapeutic efficacies, depending on the health status and age of the cell donor. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron death in the central nervous system. In this study, we isolated BM-SCs from 11 ALS patients and characterized their potential secretory capacity of neurotrophic factors. We identified significant reductions in the expression of Oct-4 and Nanog, and in the trophic factors ANG, FGF-2, HGF, IGF-1, PIGF, SDF-1α, TGF-β, and VEGF, but not in BDNF or ECGF. Migration of ALS-SCs was reduced, although the cells expressed the same markers for human mesenchymal phenotypes. These data suggest that ALS-SCs have diminished capacity as trophic mediators and may have reduced beneficial effects in cell therapy. © 2010 Mary Ann Liebert, Inc. Source

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