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Preconditioning of Mesenchymal Stem Cells Enhances the Neuroprotective Effects of Their Conditioned Medium in an
Tatiana Tolstova1, Ekaterina Dotsenko1, Natalia Luzgina1
1Institute of Biomedical Chemistry, Pogodinskaya 10, 119121 Moscow, Russia.
Background:
Alzheimer's disease (AD) develops as a result of oxidative damage to neurons and chronic inflammation of microglia. These processes can be influenced by the use of a conditioned medium (CM) derived from mesenchymal stem cells (MSCs). The CM contains a wide range of factors that have neurotrophic, antioxidant, and anti-inflammatory effects. In addition, the therapeutic potential of the CM can be further enhanced by pretreating the MSCs to increase their paracrine activity. The current study aimed to investigate the neuroprotective effects of CM derived from MSCs, which were either activated by a TLR3 ligand or exposed to CoCl2, a hypoxia mimetic (pCM or hCM, respectively), in an in vitro model of AD.
Methods:
We have developed a novel in vitro model of AD that allows us to investigate the neuroprotective and anti-inflammatory effects of MSCs on induced neurodegeneration in the PC12 cell line and the activation of microglia using THP-1 cells.
Results:
This study demonstrates for the first time that pCM and hCM exhibit more pronounced immunosuppressive effects on proinflammatory M1 macrophages compared to CM derived from untreated MSCs (cCM). This may help prevent the development of neuroinflammation by balancing the M1 and M2 microglial phenotypes via the decreased secretion of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and increased secretion of IL-4, as well as the expression of IL-10 and TGF-β by macrophages. Moreover, a previously unknown increase in the neurotrophic properties of hCM was discovered, which led to an increase in the viability of neuron-like PC12 cells under H2O2-induced oxidative-stress conditions. These results are likely associated with an increase in the production of growth factors, including vascular endothelial growth factor (VEGF). In addition, the neuroprotective effects of CM from preconditioned MSCs are also mediated by the activation of the Nrf2/ARE pathway in PC12 cells.
Conclusions:
TLR3 activation in MSCs leads to more potent immunosuppressive effects of the CM against pro-inflammatory M1 macrophages, while the use of hCM led to increased neurotrophic effects after H2O2-induced damage to neuronal cells. These results are of interest for the potential treatment of AD with CM from preactivated MSCs.
Insights
Preconditioned mesenchymal stem cell conditioned media (MSC CM) shows promise for Alzheimer's disease (AD) treatment. Activated MSC CM reduces neuroinflammation and enhances neuronal survival, offering a potential therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Immunology
Background:
- Alzheimer's disease (AD) involves neuronal oxidative damage and microglial inflammation.
- Mesenchymal stem cell conditioned medium (MSC CM) offers neurotrophic, antioxidant, and anti-inflammatory benefits.
- Preconditioning MSCs can enhance the therapeutic potential of their CM.
Purpose of the Study:
- To investigate the neuroprotective effects of MSC CM from TLR3-activated MSCs (pCM) or hypoxia-mimetic treated MSCs (hCM).
- To evaluate the impact of pCM and hCM on an in vitro AD model using PC12 and THP-1 cells.
Main Methods:
- Developed a novel in vitro AD model using PC12 and THP-1 cell lines.
- Compared the effects of pCM, hCM, and untreated MSC CM (cCM) on neurodegeneration and microglial activation.
- Assessed cytokine secretion, gene expression, and cell viability.
Main Results:
- pCM and hCM demonstrated superior immunosuppressive effects on pro-inflammatory M1 macrophages compared to cCM.
- pCM and hCM modulated microglial phenotypes towards an anti-inflammatory M2 state.
- hCM exhibited enhanced neurotrophic properties, increasing PC12 cell viability under oxidative stress.
- Neuroprotection was linked to increased VEGF production and Nrf2/ARE pathway activation.
Conclusions:
- TLR3 activation of MSCs yields CM with potent immunosuppressive effects on M1 macrophages.
- Hypoxia-mimetic treatment of MSCs produces CM with enhanced neurotrophic effects on neuronal cells.
- CM from preactivated MSCs holds potential for AD treatment by mitigating neuroinflammation and oxidative stress.
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