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High Concentrations of TNF-α Induce Cell Death during Interactions between Human Umbilical Cord Mesenchymal Stem Cells and Peripheral Blood Mononuclear Cells.

ABSTRACT: Human umbilical cord mesenchymal stromal cells (hUC-MSCs) are currently being used as novel therapeutic agents in numerous clinical trials. Previous works have shown that hUC-MSCs possess profound immunomodulatory capacities through IL-1 stimulation produced by peripheral blood mononuclear cells (PBMCs), their main cellular partner in most pathophysiological and therapeutic situations. The present study was designed to explore the role of TNF-α in these interactions. In these experiments, we demonstrated that TNF-α originated from PBMCs under the influence of IL-1. We also showed that TNF-α acted differently depending upon the concentrations reached. At low concentrations it clearly contributed to IL-6 and monocyte chemotactic protein 1 (MCP-1) production. At high concentrations, used alone or in association with the TNF-related apoptosis-inducing ligand, TNF-α also stimulated hUC-MSC IL-6 but, more intensely, MCP-1 production. This stimulation was associated but independent of apoptosis induction in a process involving Inhibitor of Apoptosis Proteins. Interferon gamma (IFN-γ), tested to stimulate PBMC and tissue activation, amplified IL-6 and MCP-1 production and cell death by, apparently, a different process involving necrosis. Our findings bring new insights into the complex interactions between hUC-MSCs and PBMCs, involving cytokines, chemokines and cell death, and are of fundamental importance for tissue homeostasis.

SUBMITTER: Li X

PROVIDER: S-EPMC4448993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAutism is a pervasive neurodevelopmental disorder. At present there are no defined mechanisms of pathogenesis and therapy is mostly limited to behavioral interventions. Stem cell transplantation may offer a unique treatment strategy for autism due to immune and neural dysregulation observed in this disease. This non-randomized, open-label, single center phase I/II trial investigated the safety and efficacy of combined transplantation of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) in treating children with autism.Methods37 subjects diagnosed with autism were enrolled into this study and divided into three groups: CBMNC group (14 subjects, received CBMNC transplantation and rehabilitation therapy), Combination group (9 subjects, received both CBMNC and UCMSC transplantation and rehabilitation therapy), and Control group (14 subjects, received only rehabilitation therapy). Transplantations included four stem cell infusions through intravenous and intrathecal injections once a week. Treatment safety was evaluated with laboratory examinations and clinical assessment of adverse effects. The Childhood Autism Rating Scale (CARS), Clinical Global Impression (CGI) scale and Aberrant Behavior Checklist (ABC) were adopted to assess the therapeutic efficacy at baseline (pre-treatment) and following treatment.ResultsThere were no significant safety issues related to the treatment and no observed severe adverse effects. Statistically significant differences were shown on CARS, ABC scores and CGI evaluation in the two treatment groups compared to the control at 24 weeks post-treatment (p < 0.05).ConclusionsTransplantation of CBMNCs demonstrated efficacy compared to the control group; however, the combination of CBMNCs and UCMSCs showed larger therapeutic effects than the CBMNC transplantation alone. There were no safety issues noted during infusion and the whole monitoring period.Trial registrationClinicalTrials.gov: NCT01343511, Title "Safety and Efficacy of Stem Cell Therapy in Patients with Autism".

Project description:Stroke is the second leading cause of death worldwide, claims six lives every 60 seconds, and is a leading cause of adult disability across the globe. Tissue plasminogen activator, the only United States Food and Drug Administration (FDA)-approved drug currently available, has a narrow therapeutic time window of less than 5 hours. In the past decade, cells derived from the human umbilical cord (HUC) have emerged as a potential therapeutic alternative for stroke; however, the most effective HUC-derived cell population remains unknown.We compared three cell populations derived from the human umbilical cord: cord blood mononuclear cells (cbMNCs); cord blood mesenchymal stromal cells (cbMSCs), a subpopulation of cbMNCs; and cord matrix MSCs (cmMSCs). We characterized these cells in vitro with flow cytometry and assessed the cells' in vivo efficacy in a 2-hour transient middle cerebral artery occlusion (MCAo) rat model of stroke. cbMNCs, cbMSCs, and cmMSCs were each transplanted intraarterially at 24 hours after stroke.A reduction in neurologic deficit and infarct area was observed in all three cell groups; however, this reduction was significantly enhanced in the cbMNC group compared with the cmMSC group. At 2 weeks after stroke, human nuclei-positive cells were present in the ischemic hemispheres of immunocompetent stroke rats in all three cell groups. Significantly decreased expression of rat brain-derived neurotrophic factor mRNA was observed in the ischemic hemispheres of all three cell-treated and phosphate-buffered saline (PBS) group animals compared with sham animals, although the decrease was least in cbMNC-treated animals. Significantly decreased expression of rat interleukin (IL)-2 mRNA and IL-6 mRNA was seen only in the cbMSC group. Notably, more severe complications (death, eye inflammation) were observed in the cmMSC group compared with the cbMNC and cbMSC groups.All three tested cell types promoted recovery after stroke, but cbMNCs showed enhanced recovery and fewer complications compared with cmMSCs.

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High Concentrations of TNF-α Induce Cell Death during Interactions between Human Umbilical Cord Mesenchymal Stem Cells and Peripheral Blood Mononuclear Cells.

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