Overexpression of GREM1 Improves the Survival Capacity of Aged Cardiac Mesenchymal Progenitor Cells via Upregulation of the ERK/NRF2-Associated Antioxidant Signal Pathway.
Overexpression of GREM1 Improves the Survival Capacity of Aged Cardiac Mesenchymal Progenitor Cells via Upregulation of the ERK/NRF2-Associated Antioxidant Signal Pathway.
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缺血性心脏病是美国死亡的主要原因。祖细胞治疗可以恢复心肌结构和功能。然而，其功效受到细胞老化和衰老的严重限制。Gremlin-1（GREM 1）是骨形态发生蛋白拮抗剂家族的成员，与细胞增殖和存活有关。然而，GREM 1在细胞衰老和衰老中的作用从未在人心脏间充质祖细胞（hMPC）中研究过。因此，本研究评估了GREM 1过表达使老化hMPC的心脏再生潜力恢复到年轻阶段并因此允许更好的心肌修复能力的假设。我们最近报道了一个具有低线粒体膜电位的hMPC亚群可以从心肌病患者的右心耳衍生细胞中分选出来，并在心肌梗死小鼠模型中表现出心脏修复能力。在这项研究中，慢病毒颗粒用于在这些hMPC中过表达GREM 1。通过Western blot和RT-qPCR评估蛋白质和mRNA表达。流式细胞仪分析膜联蛋白V/PI染色和乳酸脱氢酶测定用于评估细胞存活。观察到细胞老化和细胞衰老导致GREM 1表达减少。此外，GREM 1的过表达导致衰老基因表达的减少。GREM 1的过表达导致细胞增殖没有显著变化。然而，GREM 1似乎具有抗凋亡作用，在GREM 1过表达的hMPCs中明显的存活率增加和细胞毒性降低。过表达GREM 1还通过降低活性氧化物质和线粒体膜电位诱导细胞保护特性。这一结果与抗氧化蛋白（如SOD 1和过氧化氢酶）的表达增加以及ERK/NRF 2生存信号通路的激活有关。ERK的抑制导致GREM 1介导的细胞存活方面的再生减少，这表明可能涉及ERK依赖性途径。总之，这些结果表明，GREM 1的过表达可以使衰老的hMPC采用具有改善的存活能力的更稳健的表型，这与活化的ERK/NRF 2抗氧化信号通路相关。
Ischemic heart disease is the leading cause of mortality in the United States. Progenitor cell therapy can restore myocardial structure and function. However, its efficacy is severely limited by cell aging and senescence. Gremlin-1 (GREM1), a member of the bone morphogenetic protein antagonist family, has been implicated in cell proliferation and survival. However, GREM1’s role in cell aging and senescence has never been investigated in human cardiac mesenchymal progenitor cells (hMPCs). Therefore, this study assessed the hypothesis that overexpression of GREM1 rejuvenates the cardiac regenerative potential of aging hMPCs to a youthful stage and therefore allows better capacity for myocardial repair. We recently reported that a subpopulation of hMPCs with low mitochondrial membrane potential can be sorted from right atrial appendage-derived cells in patients with cardiomyopathy and exhibit cardiac reparative capacity in a mouse model of myocardial infarction. In this study, lentiviral particles were used to overexpress GREM1 in these hMPCs. Protein and mRNA expression were assessed through Western blot and RT-qPCR. FACS analysis for Annexin V/PI staining and lactate dehydrogenase assay were used to assess cell survival. It was observed that cell aging and cell senescence led to a decrease in GREM1 expression. In addition, overexpression of GREM1 led to a decrease in expression of senescence genes. Overexpression of GREM1 led to no significant change in cell proliferation. However, GREM1 appeared to have an anti-apoptotic effect, with an increase in survival and decrease in cytotoxicity evident in GREM1-overexpressing hMPCs. Overexpressing GREM1 also induced cytoprotective properties by decreasing reactive oxidative species and mitochondrial membrane potential. This result was associated with increased expression of antioxidant proteins, such as SOD1 and catalase, and activation of the ERK/NRF2 survival signal pathway. Inhibition of ERK led to a decrease in GREM1-mediated rejuvenation in terms of cell survival, which suggests that an ERK-dependent pathway may be involved. Taken altogether, these results indicate that overexpression of GREM1 can allow aging hMPCs to adopt a more robust phenotype with improved survival capacity, which is associated with an activated ERK/NRF2 antioxidant signal pathway.
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衰老的心脏霸权。
DOI：
10.1007/s13670-013-0064-3
发表时间：
2013-12
期刊：
Current translational geriatrics and experimental gerontology reports
影响因子：
--
作者：
Siddiqi, Sailay;Sussman, Mark A
通讯作者：
Sussman, Mark A
影响因子：
4.6
作者：
Bigarella, Carolina L.;Liang, Raymond;Ghaffari, Saghi
通讯作者：
Ghaffari, Saghi
影响因子：
30.8
作者：
Khokha, MK;Hsu, D;Harland, RM
通讯作者：
Harland, RM
影响因子：
5
作者：
Maciel, Thiago T.;Melo, Rosilene S.;Campos, Alexandre H.
通讯作者：
Campos, Alexandre H.
DOI：
10.1016/s0006-291x(02)00828-8
发表时间：
2002-08-02
影响因子：
3.1
作者：
Chen, B;Athanasiou, M;Blair, DG
通讯作者：
Blair, DG