Targeting of Deciduous Tooth Pulp Stem Cell-Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus
Targeting of Deciduous Tooth Pulp Stem Cell-Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus
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DOI：
10.4049/jimmunol.2001312
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发表时间：
2021-06-15
影响因子：
4.4
通讯作者：
Yamaza, Takayoshi
中科院分区：
文献类型：
--
作者：
Sonoda, Soichiro;Murata, Sara;Yamaza, Takayoshi
系统移植人脱落乳牙干细胞用于治疗MRL/LPR小鼠系统性红斑狼疮(SLE)样疾病。然而，这种基于棚子的疗法背后的机制仍然不清楚。在这项研究中，我们假设脱落释放细胞外小泡(SHEAD-EVS)中的营养因子可以改善MRL/LPR小鼠的SLE样表型。从大棚的培养上清液中分离出大棚EV。用RNase或不加RNase处理SHEET-EVS，并系统地给MRL/LPR小鼠。随后，从SHOAD-EV接种的MRL/LPR小鼠体内分离出骨髓间充质干细胞(BMMSCs)，检测其在体外和体内的造血生态位形成和免疫调节活性。此外，将受体骨髓间充质干细胞二次移植到MRL/LPR小鼠体内。全身输注Share-EV可改善MRL/LPR小鼠的SLE样表型，并通过挽救TERT mRNA相关的端粒酶活性、造血生态位的形成和免疫调节来改善受体BMMSCs的功能。受体BMMSCs二次移植恢复了MRL/LPR小鼠的免疫状态和肾功能。RNase处理耗尽了SHEAD-EVS中的RNA，如microRNAs，而RNA耗尽的SHEAD-EVS减弱了SHEAD-EVS在MRL/LPR小鼠中的好处。总而言之，我们的发现表明，脱落分泌的RNA，如microRNAs，通过靶向受体BMMSCs的端粒酶活性在治疗SLE中发挥关键作用。
Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) is used to treat systemic lupus erythematosus (SLE)-like disorders in MRL/lpr mice. However, the mechanisms underlying the SHED-based therapy remain unclear. In this study, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) ameliorate the SLE-like phenotypes in MRL/lpr mice. SHED-EVs were isolated from the culture supernatant of SHED. SHED-EVs were treated with or without RNase and systemically administered to MRL/lpr mice. Subsequently, recipient bone marrow mesenchymal stem cells (BMMSCs) isolated from SHED-EV-administered MRL/lpr mice were examined for the in vitro and in vivo activity of hematopoietic niche formation and immunoregulation. Furthermore, the recipient BMMSCs were secondarily transplanted into MRL/lpr mice. The systemic SHED-EV infusion ameliorated the SLE-like phenotypes in MRL/lpr mice and improved the functions of recipient BMMSCs by rescuing Tert mRNA-associated telomerase activity, hematopoietic niche formation, and immunoregulation. The secondary transplantation of recipient BMMSCs recovered the immune condition and renal functions of MRL/lpr mice. The RNase treatment depleted RNAs, such as microRNAs, within SHED-EVs, and the RNA-depleted SHED-EVs attenuated the benefits of SHED-EVs in MRL/lpr mice. Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating SLE by targeting the telomerase activity of recipient BMMSCs.