Bone Marrow Mesenchymal Stem Cells-Derived miR-21-5p Protects Grafted Islets Against Apoptosis by Targeting PDCD4.
Bone Marrow Mesenchymal Stem Cells-Derived miR-21-5p Protects Grafted Islets Against Apoptosis by Targeting PDCD4.
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DOI：
10.1093/stmcls/sxac085
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发表时间：
2023-03-02
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由于移植后胰岛丢失率高，移植胰岛的凋亡是一个亟待解决的问题。microRNA-21 - 5p（miR-21 - 5p）是骨髓间充质干细胞来源的exosomes（BMSCs-Exo）抗凋亡的重要介质，但其在胰岛移植中的作用及其分子机制尚不清楚。在这里，我们发现miR-21 - 5p可以通过BMSCs-Exo递送到胰岛细胞。随后，我们证明了miR-21 - 5p过表达减少了胰岛和INS-1细胞的凋亡，而miR-21 - 5p抑制增强了凋亡。进行了涉及RNA测序和生物信息学分析的机制分析，以确定miR-21 - 5p与其靶基因程序性细胞死亡4（PDCD4）之间的相互作用，并通过双荧光素酶测定进一步验证。在体内，过表达miR-21 - 5p的移植胰岛具有较高的存活率、较好的胰岛素分泌功能和较低的凋亡率。总之，这些结果表明，来自BMSCs-Exo的miR-21 - 5p通过抑制PDCD4表达来防止移植胰岛的凋亡。因此，miR-21 - 5p可用作无细胞治疗剂以在胰岛移植的早期阶段最小化β细胞凋亡。我们证明了BMSC可以将含有miR-21 - 5p的外泌体递送到胰岛细胞中。然后，我们发现miR-21 - 5p过表达减弱了胰岛和大鼠胰岛素瘤（INS-1）细胞的凋亡，而miR-21 - 5p抑制显著促进了凋亡。上调的miR-21 - 5p直接结合PDCD4的3'UTR，从而减少移植胰岛中的细胞凋亡。本研究证实了以往研究的结果，提示miR-21 - 5p可作为治疗剂，在胰岛移植早期最大限度地减少β细胞凋亡，从而改善移植结局。
The apoptosis of grafted islets is an urgent problem due to the high rate of islet loss soon after transplantation. MicroRNA-21-5p (miR-21-5p) is an essential mediator of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exo) during anti-apoptosis, but its effect and the underlying molecular mechanism in islet transplantation remain partially understood. Here, we found that miR-21-5p could be delivered to islet cells via BMSCs-Exo. Subsequently, we demonstrated that miR-21-5p overexpression reduced apoptosis in islets and INS-1 cells, whereas miR-21-5p inhibition enhanced apoptosis. A mechanistic analysis involving RNA sequencing and bioinformatic analysis was performed to determine the interaction between miR-21-5p and its target gene programmed cell death 4 (PDCD4), which was further verified by a dual luciferase assay. In vivo, the grafted islets overexpressing miR-21-5p showed a higher survival rate, better insulin secretion function, and a lower apoptosis rate. In conclusion, these results demonstrated that miR‑21‑5p from BMSCs-Exo protects against the apoptosis of grafted islets by inhibiting PDCD4 expression. Hence, miR-21-5p can be used as a cell-free therapeutic agent to minimize β-cell apoptosis at the early stage of islet transplantation. We demonstrated that BMSCs could deliver exosomes containing miR-21-5p into islet cells. Then, we found that miR-21-5p overexpression attenuated apoptosis of islets and rat insulinoma (INS-1) cells, while miR-21-5p inhibition significantly promoted apoptosis. The upregulated miR-21-5p directly binds to the 3'UTR of PDCD4, thereby reducing apoptosis in transplanted islets. This study confirms the results of previous studies, suggesting that miR-21-5p can be used as a therapeutic agent to minimize β-cell apoptosis in the early stage of islet transplantation and thus improve the transplantation outcome.
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影响因子：
29
作者：
Coate KC;Cha J;Shrestha S;Wang W;Gonçalves LM;Almaça J;Kapp ME;Fasolino M;Morgan A;Dai C;Saunders DC;Bottino R;Aramandla R;Jenkins R;Stein R;Kaestner KH;Vahedi G;HPAP Consortium;Brissova M;Powers AC
通讯作者：
Powers AC
影响因子：
3.9
作者：
Nie, Wei;Ma, Xiaoqian;Wang, Wei
通讯作者：
Wang, Wei
影响因子：
5.2
作者：
de Klerk E;Hebrok M
通讯作者：
Hebrok M
影响因子：
12.4
作者：
Liang Y;Duan L;Lu J;Xia J
通讯作者：
Xia J
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影响因子：
18.9
作者：
Fan L;Guan P;Xiao C;Wen H;Wang Q;Liu C;Luo Y;Ma L;Tan G;Yu P;Zhou L;Ning C
通讯作者：
Ning C