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BDNF-overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro.

ABSTRACT: The use of neurotrophic factors as therapeutic agents for neurodegenerative diseases is considered as an approach aimed at restoring and maintaining neuronal function in the peripheral and central nervous system. Since the neuroprotective effect is depending on chronic delivery of the neurotrophic factors a sustained application, e.g., via cell-based delivery is necessary. Human mesenchymal stem cells (hMSCs) were lentivirally modified to overexpress brain-derived neurotrophic factor (BDNF) and to express fluorescent marker genes for easy visualization. Since genetically modified cells should be site-specifically retained (e.g., by encapsulation) in the patients to avoid adverse effects the cells were additionally differentiated to chondrocytes to hypothetically improve their vitality and survival in a delivery matrix. Different polycations for lentiviral transduction were investigated for their efficiency. The success of differentiation was determined by analysis of chondrocyte marker genes and the neuroprotective effect of BDNF-overexpressing cells was exemplarily investigated on neurons of the peripheral auditory system. The genetically modified hMSCs overexpressed BDNF from under 1 to 125 ng ml-1 day-1 depending on the donor and transfection method. Using protamine sulfate the transfection efficacy was superior compared to the use of polybrene. The BDNF secreted by the MSCs was significantly neuroprotective in comparison to the relevant controls even though the produced mean concentrations were lower than the effective concentrations for recombinant industrially produced proteins described in literature. The presented system of BDNF-overexpressing hMSCs is neuroprotective and is therefore considered as a promising method for sustained delivery of proteins in therapeutically relevant amounts to degenerating neuronal structures.

SUBMITTER: Scheper V

PROVIDER: S-EPMC6772136 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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BDNF-overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro.

Scheper Verena V Schwieger Jana J Hamm Anika A Lenarz Thomas T Hoffmann Andrea A

Journal of neuroscience research 20190630 11

The use of neurotrophic factors as therapeutic agents for neurodegenerative diseases is considered as an approach aimed at restoring and maintaining neuronal function in the peripheral and central nervous system. Since the neuroprotective effect is depending on chronic delivery of the neurotrophic factors a sustained application, e.g., via cell-based delivery is necessary. Human mesenchymal stem cells (hMSCs) were lentivirally modified to overexpress brain-derived neurotrophic factor (BDNF) and ...[more]

PMID: 31257632

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Project description:BackgroundsAllergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties.MethodsInduced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4+ T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4+ T cells.ResultsStable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4+ T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4+ T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4+ T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role.ConclusionIL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation.

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BDNF-overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro.

Publications

BDNF-overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro.

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