Key Takeaways & Executive Findings
- •• TIIA-pretreated MSCs significantly improve cognitive function and brain glucose metabolism in 3×Tg-AD mice, while promoting synaptic and mitochondrial recovery. • TIIA-MSCs exert superior anti-neuroinflammatory effects by inhibiting microglial activation and proinflammatory cytokine release in vitro. • The TREM2 receptor is a critical mediator of TIIA-MSC's anti-inflammatory action, as its knockdown abolishes the therapeutic benefit. • Mechanistically, TIIA-MSCs activate the TREM2/PI3K/Akt pathway to shift microglia from a proinflammatory to a neuroprotective phenotype, offering a novel therapeutic strategy for AD.
Abstract
Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our previous research revealed that compared with ordinary MSC, MSC pretreated with tanshinone IIA (TIIA), referred to as TIIA-MSC, exhibited superior anti-neuroinflammatory activity, but the mechanism of action remains unclear. To clarify the underlying mechanism, this study integrated in vitro and in vivo experiments and evaluated the therapeutic effect of TIIA-MSC in a triple-transgenic Alzheimer’s disease mouse model (3×Tg-AD mice) and explored its mechanism of action in a lipopolysaccharide (LPS)-induced BV2 microglial cell inflammation model. The results showed that TIIA-MSC could significantly improve the cognitive function of 3×Tg-AD mice, increase brain glucose metabolism levels, promote the recovery of synaptic and mitochondrial structures, and effectively alleviate neuroinflammatory responses. In vitro experiments further verified the superior inhibitory effect of TIIA-MSC on microglial cell activation and proinflammatory factor release. Mechanistic studies have indicated that the triggering receptor expressed on myeloid cells 2 (TREM2) is the key molecule that mediates this process. The knockdown of TREM2 expression significantly weakened the anti-inflammatory effect of TIIA-MSC, suggesting that TREM2 plays a central role in this process. Further analysis revealed that by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway downstream of TREM2, TIIA-MSC may promote the transformation of the functional state of microglia from mainly proinflammatory to having neuroprotective and repair properties. This study systematically revealed the molecular mechanism by which TIIA-MSC regulate microglial cell phenotypic transformation through the TREM2/PI3K/Akt pathway and exert anti-neuroinflammatory effects, providing new ideas and an experimental basis for expanding the application of MSC in the treatment of neurodegenerative diseases.
1. Introduction
Neuroinflammation is a core link in the onset and progression of neurodegenerative diseases, especially Alzheimer’s disease (AD) [1, 2], for which therapeutic options remain limited [3, 4]. In recent years, stem cell therapy based on mesenchymal stem cells (MSC), owing to their unique immune regulation and neuroprotective functions, has become important for alleviating neuroinflammation and treating diseases such as AD [5, 6]. MSC not only possess multidirectional differentiation potential and the ability to migrate directionally to the injury site [7] but also secrete various neurotrophic factors and exhibit significant anti-oxidant and anti-inflammatory activities [8]. These characteristics together establish the dominant role of MSC in the field of stem cell therapy [9].
Although stem cell therapy has great therapeutic potential, its clinical application still faces key challenges, such as insufficient targeting and a low survival rate after transplantation, which severely limit its overall efficacy [10, 11]. To overcome these bottlenecks, researchers have developed various pretreatment [12, 13] and engineering strategies [14, 15], aiming to increase the survival, directed migration and proliferation differentiation ability of stem cells, promote their efficient homing to diseased tissues, and effectively stimulate the secretion of neurotrophic factors, thereby more strongly promoting the recovery of neural function [16, 17].
Pretreatment before stem cell transplantation is key for enhancing its therapeutic effect [18, 19]. Studies have shown that pretreatment of stem cells with bioactive substances or conditions can effectively regulate their survival, homing, paracrine activity and other characteristics, thereby enhancing their therapeutic potential [12, 13, 20]. In addition, genetic engineering technology is widely applied in the context of stem cell modification, further optimizing stem cell performance through the overexpression of therapeutic genes or the knockdown of detrimental factors.
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Jingjing Wu, Ying Ge, Li Zhang, Juan Huang, Nanqu Huang, Yong Luo (2026). Tanshinone IIA-pretreated mesenchymal stem cells alleviate neuroinflammation in 3×Tg-AD mice via the TREM2/PI3K/Akt pathway. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-026-04954-1
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that mesenchymal stem cells pretreated with tanshinone IIA (TIIA-MSC) effectively alleviate neuroinflammation in a triple-transgenic Alzheimer's disease mouse model by modulating microglial phenotype via the TREM2/PI3K/Akt pathway, leading to improved cognitive function and synaptic integrity.
How does TIIA pretreatment enhance MSC therapeutic potential?
TIIA pretreatment enhances the anti-neuroinflammatory properties of MSCs, likely by priming them to secrete factors that activate the TREM2 receptor on microglia, thereby promoting a shift from proinflammatory to neuroprotective microglial states.
What role does TREM2 play in the mechanism?
TREM2 is identified as a key mediator; knockdown of TREM2 significantly reduces the anti-inflammatory effect of TIIA-MSC, indicating that TREM2 is essential for the therapeutic action.
What is the significance of the PI3K/Akt pathway?
The PI3K/Akt pathway is downstream of TREM2 and is activated by TIIA-MSC treatment, which is crucial for inducing the neuroprotective microglial phenotype and exerting anti-inflammatory effects.
What are the potential clinical implications?
This study provides a novel strategy for enhancing MSC-based therapies in neurodegenerative diseases, particularly Alzheimer's disease, by using TIIA pretreatment to boost their immunomodulatory capacity, potentially improving treatment outcomes.
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