Proficiency of Extracellular Vesicles From hiPSC-Derived Neural Stem Cells in Modulating Proinflammatory Human Microglia: Role of Pentraxin-3 and miRNA-21-5p.
Proficiency of Extracellular Vesicles From hiPSC-Derived Neural Stem Cells in Modulating Proinflammatory Human Microglia: Role of Pentraxin-3 and miRNA-21-5p.
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DOI：
10.3389/fnmol.2022.845542
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发表时间：
2022
影响因子：
4.8
通讯作者：
Shetty AK
中科院分区：
文献类型：
--
作者：
Upadhya R;Madhu LN;Rao S;Shetty AK
在小鼠巨噬细胞实验和小鼠急性神经炎症模型中，人类诱导的多能干细胞（hiPSC）来源的神经干细胞（hnsc - ev）脱落的细胞外囊泡（ev）显示出有效的抗炎特性。它们还可以在鼻内给药后迅速渗透到整个大脑，这使得它们作为治疗神经退行性疾病的自体或同种异体现成产品具有吸引力。然而，它们调节活化的人小胶质细胞以及介导hnsc - ev抗炎作用的特定蛋白质和mirna的能力尚不清楚。我们研究了hnsc - ev调节活化的人小胶质细胞的能力，并探讨了hnsc - ev中戊烷素3蛋白（PTX3）和miRNA miR-21-5p在介导抗炎作用中的作用。由hiPSCs生成的成熟小胶质细胞表达多种小胶质细胞特异性标记物。它们通过上调肿瘤坏死因子-α (TNF-α)和白细胞介素-1β (IL-1β) mRNA的表达和蛋白释放来响应脂多糖（LPS）或干扰素- γ的挑战。小胶质细胞也表现出吞噬β淀粉样蛋白（Aβ）的能力。hnsc - ev的加入降低了lps刺激的人小胶质细胞TNF-α和IL-1β mRNA的表达和TNF-α和IL-1β的释放。然而，当ev中的PTX3或miR-21-5p浓度降低时，hnsc - ev对lps刺激的小胶质细胞的抗炎活性显著降低。结果表明，hnsc - ev能够熟练地将促炎症的人小胶质细胞调节为非炎症表型，这意味着它们可以用于治疗神经退行性疾病的神经炎症。此外，PTX3和miR-21-5p在hnsc - ev抗炎活性中的作用为通过PTX3和/或miR-21-5p过表达提高hnsc - ev的抗炎作用提供了新的途径。
Extracellular vesicles (EVs) shed by human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (hNSC-EVs) have shown potent antiinflammatory properties in a mouse macrophage assay and a mouse model of acute neuroinflammation. They can also quickly permeate the entire brain after intranasal administration, making them attractive as an autologous or allogeneic off-the-shelf product for treating neurodegenerative diseases. However, their ability to modulate activated human microglia and specific proteins and miRNAs mediating antiinflammatory effects of hNSC-EVs are unknown. We investigated the proficiency of hNSC-EVs to modulate activated human microglia and probed the role of the protein pentraxin 3 (PTX3) and the miRNA miR-21-5p within hNSC-EVs in mediating the antiinflammatory effects. Mature microglia generated from hiPSCs (iMicroglia) expressed multiple microglia-specific markers. They responded to lipopolysaccharide (LPS) or interferon-gamma challenge by upregulating tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) mRNA expression and protein release. iMicroglia also exhibited proficiency to phagocytose amyloid-beta (Aβ). The addition of hNSC-EVs decreased TNF-α and IL-1β mRNA expression and the release of TNF-α and IL-1β by LPS-stimulated iMicroglia (proinflammatory human Microglia). However, the antiinflammatory activity of hNSC-EVs on LPS-stimulated microglia was considerably diminished when the PTX3 or miR-21-5p concentration was reduced in EVs. The results demonstrate that hNSC-EVs are proficient for modulating the proinflammatory human microglia into non-inflammatory phenotypes, implying their utility to treat neuroinflammation in neurodegenerative diseases. Furthermore, the role of PTX3 and miR-21-5p in the antiinflammatory activity of hNSC-EVs provides a new avenue for improving the antiinflammatory effects of hNSC-EVs through PTX3 and/or miR-21-5p overexpression.
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影响因子：
16
作者：
Lötvall J;Hill AF;Hochberg F;Buzás EI;Di Vizio D;Gardiner C;Gho YS;Kurochkin IV;Mathivanan S;Quesenberry P;Sahoo S;Tahara H;Wauben MH;Witwer KW;Théry C
通讯作者：
Théry C
影响因子：
6
作者：
Ahn SY;Sung DK;Kim YE;Sung S;Chang YS;Park WS
通讯作者：
Park WS
影响因子：
5.9
作者：
Douvaras P;Sun B;Wang M;Kruglikov I;Lallos G;Zimmer M;Terrenoire C;Zhang B;Gandy S;Schadt E;Freytes DO;Noggle S;Fossati V
通讯作者：
Fossati V
影响因子：
5.6
作者：
Kodali, Maheedhar;Castro, Olagide W.;Shetty, Ashok K.
通讯作者：
Shetty, Ashok K.
DOI：
10.1111/j.1742-4658.2010.07818.x
发表时间：
2010-10
期刊：
The FEBS journal
影响因子：
--
作者：
Buller B;Liu X;Wang X;Zhang RL;Zhang L;Hozeska-Solgot A;Chopp M;Zhang ZG
通讯作者：
Zhang ZG