Long noncoding RNA LUCAT1 enhances the survival and therapeutic effects of mesenchymal stromal cells post-myocardial infarction.
Long noncoding RNA LUCAT1 enhances the survival and therapeutic effects of mesenchymal stromal cells post-myocardial infarction.
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长链非编码RNA LUCAT1增强心肌梗死后间充质基质细胞的存活和治疗效果
DOI：
10.1016/j.omtn.2021.12.006
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发表时间：
2022-03-08
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Tao Y;Liu Q;Wu R;Xiao C;Ni C;Wang K;Hu W;Zhong Z;Zhao J;Li Q;Zhu D;Zhong S;Yu H;Zhu W;Chen J;Hu X;Wang J
骨髓间充质干细胞（MSC）移植已成为心肌梗死（MI）后心脏组织修复的一种有前途的治疗策略。然而，其治疗效果仍然很低，这主要归因于移植的MSC的低活力。最近，长链非编码RNA（lncRNA）已被报道参与多种生理和病理过程，但很少有人知道他们在MSC生存的作用。利用无偏转录组分析缺氧预处理的MSC（HP-MSC）和常氧MSC（N-MSC），我们鉴定了一种名为肺癌相关转录本1（LUCAT 1）的lncRNA。LUCAT 1敲低降低了移植MSC的存活率，并降低了基于MSC的治疗效力，如心脏功能受损、心肌细胞存活率降低和MI后纤维化增加所示。相反，LUCAT 1过表达具有相反的结果。LUCAT 1与含有jumonji结构域的6（JMJD 6）结合并募集到叉头盒Q1（FOXQ 1）的启动子，FOXQ 1在H4 R3 me 2（s）和H3 R2 me 2（a）处使FOXQ 1去甲基化，从而下调Bax表达并上调Bcl-2表达以减弱MSC凋亡。因此，我们的研究结果揭示了LUCAT 1对MSC凋亡的保护作用，并证明LUCAT 1介导的JMJD 6-FOXQ 1通路可能代表了一个新的靶点，以加强基于MSC的治疗缺血性心血管疾病的治疗效果。一种新的lncRNA LUCAT 1与JMJD 6结合并将其募集到FOXQ 1的启动子上，其在H4 R3 me 2（s）和H3 R2 me 2（a）处使FOXQ 1去甲基化，从而降低促凋亡蛋白（Bax和Cleaved caspase-3）并增加抗凋亡蛋白（Bcl-2）表达以减弱MSC凋亡。LUCAT 1介导的JMJD 6-FOXQ 1通路可能是提高MSCs治疗心肌梗死疗效的一条有前景的途径。
Mesenchymal stromal cell (MSC) transplantation has been a promising therapeutic strategy for repairing heart tissues post-myocardial infarction (MI). Nevertheless, its therapeutic efficacy remains low, which is mainly ascribed to the low viability of transplanted MSCs. Recently, long noncoding RNAs (lncRNAs) have been reported to participate in diverse physiological and pathological processes, but little is known about their role in MSC survival. Using unbiased transcriptome profiling of hypoxia-preconditioned MSCs (HP-MSCs) and normoxic MSCs (N-MSCs), we identified a lncRNA named lung cancer-associated transcript 1 (LUCAT1) under hypoxia. LUCAT1 knockdown reduced the survival of engrafted MSCs and decreased the MSC-based therapeutic potency, as shown by impaired cardiac function, reduced cardiomyocyte survival, and increased fibrosis post-MI. Conversely, LUCAT1 overexpression had the opposite results. Mechanistically, LUCAT1 bound with and recruited jumonji domain-containing 6 (JMJD6) to the promoter of forkhead box Q1 (FOXQ1), which demethylated FOXQ1 at H4R3me2(s) and H3R2me2(a), thus downregulating Bax expression and upregulating Bcl-2 expression to attenuate MSC apoptosis. Therefore, our findings revealed the protective effects of LUCAT1 on MSC apoptosis and demonstrated that the LUCAT1-mediated JMJD6-FOXQ1 pathway might represent a novel target to potentiate the therapeutic effect of MSC-based therapy for ischemic cardiovascular diseases. A novel lncRNA, LUCAT1, bound with and recruited JMJD6 to the promoter of FOXQ1, which demethylated FOXQ1 at H4R3me2(s) and H3R2me2(a), thus decreasing pro-apoptotic protein (Bax and Cleaved caspase-3) and increasing anti-apoptotic protein (Bcl-2) expression to attenuate MSC apoptosis. LUCAT1-mediated JMJD6-FOXQ1 pathway might be a promising pathway for improving MSCs’ therapeutic efficacy in MI.
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DOI：
10.1126/science.aal2512
发表时间：
2017-06-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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DOI：
10.1111/j.1582-4934.2009.00657.x
发表时间：
2009-08-01
影响因子：
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