Dexamethasone-Integrated Mesenchymal Stem Cells for Systemic Lupus Erythematosus Treatment via Multiple Immunomodulatory Mechanisms,ACS Nano

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Dexamethasone-Integrated Mesenchymal Stem Cells for Systemic Lupus Erythematosus Treatment via Multiple Immunomodulatory Mechanisms
ACS Nano ( IF 15.8 ) Pub Date : 2024-05-08 , DOI: 10.1021/acsnano.4c02420
Wenjuan Ma _{1,

2} , Junyi Che ₁ , Weiwei Chen ₁ , Dandan Wang ₁ , Huayong Zhang ₁ , Yuanjin Zhao _{1,

3}

Affiliation

The therapeutic application of mesenchymal stem cells (MSCs) has good potential as a treatment strategy for systemic lupus erythematosus (SLE), but traditional MSC therapy still has limitations in effectively modulating immune cells. Herein, we present a promising strategy based on dexamethasone liposome-integrated MSCs (Dexlip-MSCs) for treating SLE via multiple immunomodulatory pathways. This therapeutic strategy prolonged the circulation time of dexamethasone liposomes in vivo, restrained CD4⁺T-cell proliferation, and inhibited the release of proinflammatory mediators (IFN-γ and TNF-α) by CD4⁺T cells. In addition, Dexlip-MSCs initiated cellular reprogramming by activating the glucocorticoid receptor (GR) signaling pathway to upregulate the expression of anti-inflammatory factors such as cysteine-rich secretory protein LCCL-containing domain 2 (CRISPLD2) and downregulate the expression of proinflammatory factors. In addition, Dexlip-MSCs synergistically increased the anti-inflammatory inhibitory effect of CD4⁺T cells through the release of dexamethasone liposomes or Dex-integrated MSC-derived exosomes (Dex-MSC-EXOs). Based on these synergistic biological effects, we demonstrated that Dexlip-MSCs alleviated disease progression in MRL/lpr mice more effectively than Dexlip or MSCs alone. These features indicate that our stem cell delivery strategy is a promising therapeutic approach for clinical SLE treatment.

中文翻译：

地塞米松整合间充质干细胞通过多种免疫调节机制治疗系统性红斑狼疮

间充质干细胞（MSC）的治疗应用作为系统性红斑狼疮（SLE）的治疗策略具有良好的潜力，但传统的间充质干细胞疗法在有效调节免疫细胞方面仍然存在局限性。在此，我们提出了一种基于地塞米松脂质体整合 MSC（Dexlip-MSC）的有前景的策略，用于通过多种免疫调节途径治疗 SLE。该治疗策略延长了地塞米松脂质体在体内的循环时间，抑制了CD4 ⁺ T细胞的增殖，并抑制了CD4 ⁺ T细胞释放促炎介质（IFN-γ和TNF-α）。此外，Dexlip-MSCs通过激活糖皮质激素受体（GR）信号通路启动细胞重编程，上调富含半胱氨酸的分泌蛋白LCCL含结构域2（CRISPLD2）等抗炎因子的表达，并下调促炎因子的表达。此外，Dexlip-MSCs通过释放地塞米松脂质体或Dex整合的MSC衍生的外泌体（Dex-MSC-EXOs）协同增强CD4 ⁺ T细胞的抗炎抑制作用。基于这些协同生物效应，我们证明 Dexlip-MSC 比单独使用 Dexlip 或 MSC 更有效地减轻 MRL/lpr 小鼠的疾病进展。这些特征表明我们的干细胞递送策略是临床 SLE 治疗的一种有前景的治疗方法。

更新日期：2024-05-08

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