Administration Of MSCs Research Articles

Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo.

Mesenchymal stem cells/multipotent stromal cells (MSCs) are promising therapeutics for a variety of conditions. However, after transplantation, cell retention remains extremely challenging. Given that many hypoxic signals are transitory and that the therapeutic administration of MSCs is typically into tissues that are normally hypoxic, we studied the effect of hypoxic preconditioning (HP) prior to new exposure to hypoxia. We show that preincubation for 2 days or more in 1% oxygen reduces serum deprivation-mediated cell death, as observed by higher cell numbers and lower incorporation of EthD-III and Annexin V. Consistently, HP-MSCs expressed significantly lower levels of cytochrome c and heme oxygenase 1 as compared to controls. Most importantly, HP-MSCs showed enhanced survival in vivo after intramuscular injection into immune deficient NOD/SCID-IL2Rgamma(-/-) mice. Interestingly, HP-MSCs consume glucose and secrete lactate at a slower rate than controls, possibly promoting cell survival, as glucose remains available to the cells for longer periods of time. In addition, we compared the metabolome of HP-MSCs to controls, before and after hypoxia and serum deprivation, and identified several possible mediators for HP-mediated cell survival. Overall, our findings suggest that preincubation of MSCs for 2 days or more in hypoxia induces metabolic changes that yield higher retention after transplantation.

Effect of subconjunctival injection of mesenchymal stem cells on corneal allograft survival

Background Mesenchymal stem cells (MSCs) have been applied in basic and clinical researches of organ transplantation.Our previous study showed that intravenous injection of MSCs prolonged corneal allograft survival in rat.However, the effect of local administration of MSCs on corneal allograft rejection remains unclear. Objective The aim of this study was to investigate the effect of subconjunctival injection of MSCs on corneal allograft rejection in rat model of keratoplasty. Methods MSCs were isolated and cultured from femur and tibia bone marrow of clean Wistar rats, and then the cells were identified by induced differentiation of osteoblast and adipocyte.The third generation of MSCs was used in subsequent experiment.Allogenic penetrating keratoplasty was performed with the bilateral corneas of 20 Wistar rats as donor grafts and the right eyes of 40 Lewis rats as recipients.PBS 0.1 ml containing 2×106 MSCs and 0.1 ml PBS only was subconjunctivally injected immediately and postoperative 3 days respectively in randomized two groups, and another 6 normal Lewis rats served as the normal control group.Corneal rejection response was evaluated under the slit lamp after surgery based corneal opacity, edema and neovascularization, and the grafts were scored according to the criteria of Larkin.The corneal samples were extracted from 12 rats of the PBS control group and the MSCs group separately 10 days after surgery.The relative expressions of Th1 cytokines (interferon-γ [IFN γ] mRNA and interleukin-2 mRNA) and Th2 cytokines (IL-4 mRNA and IL-10 mRNA) were detected by real-time quantitative PCR.Protein levels of IL-4 and IL-10 proteins in the corneas were assayed by ELISA.All experimental protocols involving rats were approved by the laboratory animal care and use committee of the Tianjin Medical University and treated with the ARVO statement for the use of animals in ophthalmic and vision research. Results The cells grew well with the orange stain for alizarin red in differentiated the osteoblasts and red stain for Oil red O in differentiated adipocytes.The survival time of corneal graft in the MSCs group was (11.8±1.6) days, it was significantly longer than (9.6±1.4) days in the PBS control group (P=0.004). The levels of IL-4 mRNA and IL-10 mRNA in the MSCs group were significantly higher than those in the PBS control group (both at P=0.00); while the levels of IFN-γ mRNA and IL-2 mRNA were not significantly different between the groups (both at P>0.05). The IL-10 protein contents were (22.74±7.06), (68.40±12.83) and (215.41±44.66)pg/ml in the normal control group, PBS control group and MSCs group, showing significant difference among the three groups (F=55.06, P=0.00) and a significant increase in the MSCs group compared with the PBS control group and the normal control group (both at P<0.05). Conclusions Subconjunctival injection of MSCs prolongs the survival time of cornea allograft in penetrating keratoplasty probably by modulating the balance between Th1 and Th2 cytokines, especially by up-regulating Th2 cytokines. Key words: Mesenchymal stem cell transplantation; Corneal transplantation; Graft survival/immunology; T-lmphocytes; Interferon-gamma; Interleukin; Rats, Lewis

Local administration of non-diabetic MSCs to diabetic femoral fractures enhances callus remodelling and deposition of reparative bone

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Intrathecal Autologous Bone Marrow Derived Mesenchymal Stem Cells for Ischemic Stroke: Short Term Safety and Efficacy Study

Background: Preclinical and animal studies provide considerable hope for stem cell therapy in cerebrovascular stroke. This study was designed as a pilot study to explore this provisional data. Autologous bone marrow derived mesenchymal stem cells were chosen due to their proven angiogenic, paracrine and neuroregenerative functions. Subjects and Methods: The present study included 32 patients with ischemic stroke fulfilling the following criteria: Inclusion Criteria: 1. Patients with established stroke in the distribution of the middle cerebral artery territory. 2. Six months at least after the onset of acute ischemic stroke. 3. CT brain at the onset denoting acute ischemic stroke. Exclusion Criteria: 1. Hemorrhagic stroke. 2. Conditions which mimick stroke,e.g., multiple sclerosis, vasculitis, arteriovenous malformations, trauma, tumours. Patients were randomly divided into control group (11 patients) and study group (21 patients) which was further divided according to the time between the onset of the stroke and the beginning of the study into: Group I : onset of the stroke and the beginning of the study :6-12 months( 12 patients: 6 males and 6 females). Group II: onset of stroke and the beginning of the study :13-36 months (9 patients: 5 males and 4 females). Control Group: 11 stroke patients : 6 males and 5 females. Time from onset of stroke to beginning of the study ranged from 6-30 months. Both study and control group were subjected to thorough clinical and laboratory assessment , CT brain, National institutes of Health Stroke Scale (NIHSS) and th Barthel active daily life (ADL) scale at the start of therapy, and at 1,3,6 and 12 months after the start of therapy. Stem Cell Injection: 10 million autologous bone marrow-derived MSCs were injected via lumbar puncture in the study group. Results and Conclusions: Changes in Follow-up Parameters: 1. Changes in NIHSS score: Control group showed non-significant decrease in NIHSS score starting from the 3rd month. On the other hand, study group showed highly significant decrease in NIHSS score starting from 6th month, more in group I. 2. Changes in ADL score: ADL score showed non-significant increase starting from 3rd month in the control group, while it showed a highly significant increase in the study group starting from 6th month, more pronounced in group I. Intrathecal administration of MSCs is safe and enhances regeneration in ischemic stroke patients.

Mesenchymal stem cells alleviate atherosclerosis by elevating number and function of CD4(+)CD25 (+)FOXP3 (+) regulatory T-cells and inhibiting macrophage foam cell formation.

Atherosclerosis is a chronic inflammatory disease characterized by the formation of plaques inside arteries, leading to narrowing and blockage. Potential therapeutic strategies include expanding the population of regulatory T-cells (Tregs) to enhance atheroprotective immunity, and inhibiting the formation of macrophage foam cells. Here, we studied the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) on atherosclerotic plaque formation in Apolipoprotein E(-/-) (ApoE-KO) mice, and elucidated the underlying mechanism. BM-MSCs isolated from 4 week-old ApoE-KO mice were evaluated by flow cytometry for expression of MSC-specific markers. Thirty eight week-old ApoE-KO mice were randomly divided into three experimental groups (n = 10 per group): 1. MSC group-received BM-MSCs intravenously; 2. Vehicle group-received DMEM; 3. Control group-did not receive any treatment. Administration of MSCs resulted in a marked decrease in the size of atherosclerotic plaques 3 months after treatment. In addition, the number and function of CD4(+)CD25(+)FOXP3(+) regulatory T-cells (Tregs) in cultured splenocytes, and the expression of FOXP3 at both mRNA and protein levels, was significantly increased in the MSC group. In vitro experiments further indicated that the formation of macrophage foam cells was inhibited by treatment with MSCs, accompanied by a significant downregulation in CD36 and scavenger receptor A (SRA). Our findings suggest that MSCs play an atheroprotective role by enhancing the number and function of Tregs and inhibiting the formation of macrophage foam cells. Hence, administration of MSCs to atherosclerotic patients might have significant clinical benefits.

A pregnancy case report of alagille syndrome; expression of NOTCH signaling in the placenta

A pregnancy case report of alagille syndrome; expression of NOTCH signaling in the placenta

Human mesenchymal stem/stromal cells prevent experimental autoimmune uveitis by inhibiting Th17 cells and by inducing IL-10-expressing B220+CD19+ cells (MUC7P.759)

Abstract Mesenchymal stem/stromal cells (MSCs) have the remarkable ability to protect tissues by modulating immune responses in various autoimmune diseases. We here investigated that systemic administration of MSCs might prevent development of experimental autoimmune uveitis (EAU) in mice. The study was conducted in conformance with the FASEB Statement of Principles for the use of animals in research and education. Analysis of the retina during the efferent phase revealed that a single intraperitoneal injection of human bone marrow-derived MSCs (hMSCs) at the time of immunization markedly protected the retina from inflammation-mediated damage and suppressed levels of innate and adaptive pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, IFN-γ, IL-17A, and IL-2 in the eye. Analysis of draining lymph nodes (DLNs) during the afferent phase showed that hMSCs significantly decreased the proportions of IL-17- or IFN-γ-expressing CD4+ T cells as well as levels of their cytokines, IL-17A and IFN-γ. The levels of IL-1β, IL-6, IL-12, and IL-23 were not decreased by hMSCs. However, hMSCs significantly increased the level of immunoregulatory cytokine IL-10 and markedly induced the population of IL-10+B220+CD19+ cells in DLNs. Together, data demonstrate that systemic administration of hMSCs attenuates EAU by inducing IL-10-secreting B220+CD19+ cells and by suppressing the Th1/Th17 immune responses.

Allo-Reactivity of Mesenchymal Stem Cells in Rhesus Macaques Is Dose and Haplotype Dependent and Limits Durable Cell Engraftment In Vivo

The emerging paradigm that MSCs are immune privileged has fostered the use of “off-the-shelf” allogeneic MSC-based therapies in human clinical trials. However, this approach ignores studies in experimental animals wherein transplantation of MSCs across MHC boundaries elicits measurable allo-immune responses. To determine if MSCs are hypo-immunogeneic, we characterized the immune response in rhesus macaques following intracranial administration of allogeneic vs. autologous MSCs. This analysis revealed unambiguous evidence of productive allo-recognition based on expansion of NK, B and T cell subsets in peripheral blood and detection of allo-specific antibodies in animals administered allogeneic but not autologous MSCs. Moreover, the degree of MHC class I and II mismatch between the MSC donor and recipient significantly influenced the magnitude and nature of the allo-immune response. Consistent with these findings, real-time PCR analysis of brain tissue from female recipients administered varying doses of male, allogeneic MSCs revealed a significant inverse correlation between MSC engraftment levels and cell dose. Changes in post-transplant neutrophil and lymphocyte counts also correlated with dose and were predictive of overall MSC engraftment levels. However, secondary antigen challenge failed to elicit a measurable immune response in allogeneic recipients. Finally, extensive behavior testing of animals revealed no main effect of cell dose on motor skills, social development, or temperament. Collectively, these data indicate that allogeneic MSCs are weakly immunogenic when transplanted across MHC boundaries in rhesus macaques and this negatively impacts durable engraftment levels. Therefore the use of unrelated donor MSCs should be carefully evaluated in human patients.

Fluoroscopy assisted minimally invasive transplantation of allogenic mesenchymal stromal cells embedded in HyStem reduces the progression of nucleus pulposus degeneration in the damaged ntervertebral [corrected] disc: a preliminary study in rabbits.

This study was conducted to develop a technique for minimally invasive and accurate delivery of stem cells to augment nucleus pulposus (NP) in damaged intervertebral discs (IVD). IVD damage was created in noncontiguous discs at L4-L5 level; rabbits (N = 12) were randomly divided into three groups: group I treated with MSCs in HyStem hydrogel, group II treated with HyStem alone, and group III received no intervention. MSCs and hydrogel were administered to the damaged disc under guidance of fluoroscopy. Augmentation of NP was assessed through histological and MRI T2 mapping of the NP after eight weeks of transplantation. T2 weighted signal intensity was higher in group I than in groups II and III (P < 0.05). Disc height index showed maximum disc height in group I compared to groups II and III. Histological score of the degenerative index was significantly (P < 0.05) lower in group I (8.6 ± 1.8) than that in groups II (11.6 ± 2.3) and III (18.0 ± 5.7). Immunohistochemistry staining for collagen type II and aggrecan staining were higher in group I as compared to other groups. Our results demonstrate that the minimally invasive administration of MSCs in hyaluronan hydrogel (HyStem) augments the repair of NP in damaged IVD.

Reflection of stem cell therapy: An epilogue to the ‘Stem cells and the lung’ review series

Reflection of stem cell therapy: An epilogue to the ‘Stem cells and the lung’ review series

The Anti-Inflammatory Mechanism of Action of a Water Soluble Curcumin Derivative and Mscs in Alzheimer Disease Induced In Rats

The objective is to evaluate the possible mechanisms of action of a water soluble curcumin derivative and MSCs in Alzheimer disease (AD). Materials and Methods: This work included: Seventy rats which were divided equally into: control group, AD group (induced by lipopolysaccharide), AD group received a novel curcumin derivative (NCD), AD group received pure curcumin, AD group received MSCs then NCD, AD group received MSCs, AD group received MSCs with NCD. Histopathological examination and estimation of serum IL-10 and IL-6 by ELISA, estimation of MDA and GSH in brain tissue by colorimetry and estimation of tissue cholesterol were performed. Results: Histopathological examination of brain tissue from AD animals revealed the presence of plaques. Administration of MSCs or MSCs with NCD into rats after induction of experimental AD improved the histopathological picture with plaque disappearance, while other groups showed decrease of plaque formation. Levels of IL-10 were increased while of IL-6 were decreased in all treated groups. MDA and cholesterol levels were decreased while GSH levels were increased in all treated groups.Conclusion: Administration of BM-derived MSCs either alone or with the NCD exert a therapeutic effect on the brain lesion in Alzheimer’s disease. This effect may be through the anti-inflammatory and antioxidant action of both MSCs and curcumin. These data suggests that MSCs and curcumin may be a therapeutic target in treatment of AD.

The effect of mesenchymal stem cells on dynamic changes of T cell subsets in experimental autoimmune uveoretinitis

Mesenchymal stem cells (MSCs) are being explored extensively as a promising treatment for autoimmune diseases. We have recently reported that MSCs could ameliorate experimental autoimmune uveoretinitis (EAU) in rats. In this study, we examined further the effects of MSCs on the dynamics of T cell subsets in both eye and spleen and their cytokine production during the course of EAU. We focused on when and where the MSCs had inhibitory effects on T helper type 1 (Th1) and Th17 cells and how long the inhibitory effect lasted, in order to provide more mechanistic evidence for MSCs on the treatment of uveitis. Compared to the control group, administration of MSCs decreased the production of Th1 and Th17 cytokines significantly, while the production of Th2 and regulatory T cell (T(reg)) cytokines [interleukin (IL)-10 and transforming growth factor (TGF)-β] was elevated during the entire course of EAU. Correspondingly, the dynamic levels of IL-17 in the aqueous humour (AqH) were reduced in MSC-treated rats. Moreover, the ratio of Th17/T(reg) cells in both spleen and eye was decreased. These results provide powerful evidence that MSCs can regulate negatively both Th1 and Th17 responses and restore the balance of Th17/T(regs) in the whole course of EAU, which is important for the regression of the disease.

Genetically Engineered Mesenchymal Stem Cells that Overexpress ACE2 or Angiotensin‐(1–7) Show Enhanced Nitric‐Oxide Production

Administration of MSCs has been proposed for the treatment of cardiopulmonary diseases. This study was undertaken to determine whether overexpression of Angiotensin converting enzyme2 (ACE2) or Angiotensin‐(1–7) [Ang‐(1–7)] could enhance the production of nitric oxide (NO). MSCs were isolated from the femur and tibial bones of male SD rats. The cultured cells tested positive for the surface markers CD44 and CD90, and negative for CD34 and CD45 by flow cytometry. Also, they differentiated into adipocytes, confirming their mesenchymal stem cell origin. Passage‐3 MSCs were engineered to overexpress ACE2, Ang‐(1–7) or GFP following lentiviral vector‐mediated transduction. Quantitative real time PCR showed significant elevation in ACE2 levels in infected cells. Also, enzymatic assays and ELISA confirmed increased activity of ACE2 and secreted levels of Ang‐(1–7) respectively. After 72hrs of infection, the bathing medium was collected to determine NO levels using the Griess reagent system. NO production was significantly increased in MSCs overexpressing ACE2 and Ang‐(1–7) as compared with GFP or uninfected cells ( Uninfected MSCs: 4.6+0.7μM; GFP‐MSCs: 3.7+0.3μM; ACE2‐MSCs: 6.7+0.3μM Ang‐(1–7)‐MSCs: 8+0.5μM; p&lt;0.05). These results suggest that ACE2/Ang‐(1–7) stimulates the basal production of NO in MSCs, which could enhance their therapeutic potential for the treatment of cardiopulmonary diseases.

Intravenous Mesenchymal Stem Cells Improve Survival and Motor Function in Experimental Amyotrophic Lateral Sclerosis

Despite some advances in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis, significant achievements in treating this disease are still lacking. Mesenchymal stromal (stem) cells (MSCs) have been shown to be effective in several models of neurological disease. To determine the effects of the intravenous injection of MSCs in an ALS mouse model during the symptomatic stage of disease, MSCs (1 × 10⁶) were intravenously injected in mice expressing human superoxide dismutase 1 (SOD1) carrying the G93A mutation (SOD1/G93A) presenting with experimental ALS. Survival, motor abilities, histology, oxidative stress markers and [³H]D-aspartate release in the spinal cord were investigated. MSC injection in SOD1/G93A mice improved survival and motor functions compared with saline-injected controls. Injected MSCs scantly home to the central nervous system and poorly engraft. We observed a reduced accumulation of ubiquitin agglomerates and of activated astrocytes and microglia in the spinal cord of MSC-treated SOD1/G93A mice, with no changes in the number of choline acetyltransferase- and glutamate transporter type 1-positive cells. MSC administration turned around the upregulation of metallothionein mRNA expression and of the activity of the antioxidant enzyme glutathione S-transferase, both associated with disease progression. Last, we observed that MSCs reverted both spontaneous and stimulus-evoked neuronal release of [³H]D-aspartate, a marker of endogenous glutamate, which is upregulated in SOD1/G93A mice. These findings suggest that intravenous administration of MSCs significantly improves the clinical outcome and pathological scores of mutant SOD1/G93A mice, thus providing the rationale for their exploitation for the treatment of ALS.

Therapeutic factors secreted by mesenchymal stromal cells and tissue repair

Systemic administration of MSCs resulted in remarkable functional improvements in injured tissues without either long-term engraftment or differentiation in many clinical and experimental situations. Emerging evidence suggest that most of the beneficial effects of MSCs could be explained by secretion of soluble factors that have multiple effects including modulation of inflammatory and immune reactions, protection from cell death, and stimulation of endogenous progenitor cells. In this review, we focus on the therapeutic factors that account for the beneficial effects of MSCs in animal models of human diseases.

Topical application of mesenchymal stem cells effectively reduces corneal surface inflammation by inhibiting Th17 T cells proliferation in mouse chemical burn model (147.16)

Abstract Mesenchymal stem cells(MSCs) has known to have antiinflammatory properties in various inflammatory disease models, however the in vivo effect of MSCs on the inflammation is variable depending on the administration site for the in vivo delivery. To investigate the mechanism of antiinflammatory effect of topical application of MSCs on chemcal burn model, and to compare whether the effect of systemic application of MSCs is the same as topical introduction of MSCs, we made mouse chemical burn model, delivered MSCs, and evaluated local and systemic changes. It had been conducted in conformance with the FASEB Statement of Principles for the use of animals in research and education. We found that topical application of MSCs reduced corneal inflammation in mouse chemical burn model, however, systemic administration of MSCs could not decrease corneal inflammation in the same model. Direct application of MSCs to inflammatory corneal surface diminished not only infiltration of inflammatory cells in the cornea but also Th17 cells in the draining lymph nodes, on the other hand, systemic administration of MSCs did not. It suggested that systemic application of MSC might not effectively reach the target organ (eye) or the draining lymph nodes, and implied that adequate administration of MSCs might be crucial to maximize efficient antiinflammatory property of MSCs in various inflammatory disesase models.

1100 PROLONGED GLUCOCORTICOID EXPOSURE RESULTS IN THE APPEARANCE OF HEPATOCYTES IN THE ADULT PANCREAS

6bone marrow-derived MSCs were administered, either intravenously (i.v.) through the tail vene or locally in the capsule of one of the 2 remaining fibrotic liver lobes. After 8 days the mice were sacrificed and the completely regenerated livers removed. Results: Histochemical analyses, by routine histology and Sirius red staining of the collagen deposition, revealed that in the liver lobes of control animals (n = 7) no fibrotic septa or lobuli were present. In the hepatectomized liver parts (n = 89) of the CCL4-treated animals the fibrotic septa/lobuli formation was 66±3%. In the CCL4-treated control group (n = 13) fibrotic septa/lobuli in both regenerated lobes was 15±4% and 18±5%. Intravenous administration of MSCs (n = 8) had resulted in a significantly (P < 0.05) increased fibrotic septa/ lobuli formation, i.e., 28±6% and 33±6% of the regenerated lobes. Remarkably, local administration of MSCs in the capsule (n = 7) resulted in a significantly (P < 0.05) decreased fibrosis of the septa/ lobuli to 8±2% of that liver lobe. In the counterpart liver lobe, which received no local MSCs, the fibrosis formation was 22±8%, comparable to the CCL4 controls and somewhat lower (ns) than in the MSCs-i.v. group. Conclusions: Local administration of MSCs to liver lobes resulted in an almost normal regenerated liver, but not in the in situ liver counterpart, whereas intravenous administration of MSCs significantly increased fibrosis in the regenerated livers. These observations indicate that the route of MSC administration determines the effect on the fibrotic process in the liver.

Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model

Allogeneic human mesenchymal stem cells (hMSCs) introduced intravenously can have profound anti-inflammatory activity resulting in suppression of graft vs. host disease as well as regenerative events in the case of stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of these diseases. hMSCs produce bioactive factors that provide molecular cuing for: 1) immunosuppression of T cells; 2) antiscarring; 3) angiogenesis; 4) antiapoptosis; and 5) regeneration (i.e., mitotic for host-derived progenitor cells). Studies have shown that hMSCs have profound effects on the immune system and are well-tolerated and therapeutically active in immunocompetent rodent models of multiple sclerosis and stroke. Furthermore, intravenous administration of MSCs results in pulmonary localization. Asthma is a major debilitating pulmonary disease that impacts in excess of 150 million people in the world with uncontrolled asthma potentially leading to death. In addition, the socioeconomic impact of asthma-associated illnesses at the pediatric and adult level are in the millions of dollars in healthcare costs and lost days of work. hMSCs may provide a viable multiaction therapeutic for this inflammatory lung disease by secreting bioactive factors or directing cellular activity. Our studies show the effectiveness and specificity of the hMSCs on decreasing chronic airway inflammation associated with the murine ovalbumin model of asthma. In addition, the results from these studies verify the in vivo immunoeffectiveness of hMSCs in rodents and support the potential therapeutic use of hMSCs for the treatment of airway inflammation associated with chronic asthma.

Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: Focusing on neuroprotective effects of stromal cell-derived factor-1α

BackgroundMesenchymal stem cells (MSCs) are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1α (SDF-1α) is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1α were explored. 6-hydroxydopamine (6-OHDA, 20 μg) was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 × 107 cells, respectively) or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1α were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA) assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining.ResultsRats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH)-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc) compared to that of control rats. In the in vitro study, SDF-1α treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups.ConclusionsConsequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1α. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.

Tumor-derived mesenchymal stem cells enhance tumor development via nitric oxide (100.33)

Abstract Mesenchymal stem cells (MSCs) have been widely applied in treating immune disorders due to their immunosuppressive capacity. However, a major concern for the clinical application of MSCs is their risk to promote tumorigenesis. In the meantime, there are increasing reports about the identification of MSCs from various tumor tissues. In this study, we compared the tumor-derived MSCs with bone marrow-derived MSCs (BM-MSCs) in vitro and in vivo. We found that only tumor-derived MSCs, but not BM-MSCs enhance tumor development. In vitro, tumor-derived MSCs had a similar capacity to suppress T cell receptor-induced T cell proliferation via nitric oxide (NO), but exhibited a more vigorous inhibition on the differentiation and maturation of dendritic cells, compared to BM-MSCs. Moreover, co-culture with tumor-derived MSCs led bone marrow cells to differentiate into more CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), another NO-producing immunosuppressive cell population. In vivo, more MDSCs were also detected after administration of tumor-derived MSCs, but not BM-MSCs in tumor-bearing mice. Furthermore, tumor-derived MSCs, but not BM-MSCs significantly enhanced tumor growth, which was partially dependent on NO. Therefore, NO-dependent tumor promoting effect is likely not mediated by MSCs themselves, but through the indirect action of MDSCs. Our findings indicate a novel role of MSCs in tumor progression and provide new information for the clinical application of MSCs.