Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production.
Identification of a CTRP9 C-Terminal polypeptide capable of enhancing bone-derived mesenchymal stem cell cardioprotection through promoting angiogenic exosome production.
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DOI：
10.1016/j.redox.2021.101929
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发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Liu D;Gu G;Gan L;Yan W;Zhang Z;Yao P;Zhu D;Lau WB;Xie D;Wu S;Meng Z;Tsukuda J;Christopher T;Lopez B;Zhao J;Gao E;Koch W;Ma XL;Wang Y
间充质干细胞治疗通过尚未完全了解的机制改善缺血性心力衰竭。C1q-肿瘤坏死因子α相关蛋白-9(CTRP9)是一种新型的抗氧化性心脏因子，通过其c-末端的活性球状结构域(GCTRP9)能够改善局部微环境和细胞存活。目前的研究试图：1)鉴定具有干细胞保护功能的活性gCTRP9 c-末端多肽；2)确定铅多肽是否能使/增强皮质骨间充质干细胞(CBSC)对心肌梗死后重构的心脏保护作用；3)确定相关的潜在细胞/分子机制。利用I-tasser结构预测和三维活性中心模拟，我们克隆和纯化了3个gCTRP9片段(CTRP9-237、CTRP9-277和CTRP9-281)。比较了它们与gCTRP9对细胞挽救蛋白的激活。在这三个片段中，CTRP9-281(一种含有45个残基的多肽)与gCTRP9相比，具有相当或更强的ERK1/2活性。CTRP9-281或gCTRP9可显著促进CBSC的增殖和迁移，减轻氧化应激诱导的CBSC凋亡。CTRP9-281和gCTRP9可上调SOD2和SOD3的表达。然而，CTRP9-281上调FGF2和VEGFA的表达/分泌依赖ERK1/2，而不是gCTRP9。单独应用gCTRP9或CTRP9-281可减轻心肌梗死后的心功能障碍，并以类似的方式改善梗死心脏中的CBSC滞留。然而，CTRP9-281与CBSC在促血管生成、抗纤维化和抗重塑作用方面的协同作用强于gCTRP9。机制上，CTRP9-281显著增加CBSC富含SOD2和VEGFA的外切体产量。经CTRP9-281处理的CBSC外切体在体外可显著减轻氧化应激诱导的心肌细胞凋亡。外切体生成抑制剂可减弱CTRP9-281对CBSC在体心脏保护的增强作用。我们发现了一种CTRP9多肽，它能上调SOD2/SOD3的表达，并改善CBSC的存活/保留，类似于gCTRP9。此外，CTRP9-281通过CBSC刺激富含VEGFA的外切体的产生，发挥优越的促血管生成、抗纤维化和心脏保护作用。CTRP9-281在CBSC的抗氧化基因表达方面与gCTRP9相当，并能促进CBSC的存活/保留。CTRP9-281与CBSC在促进缺血心脏血管生成和抗纤维化方面具有较好的协同作用。CTRP9-281显著增强CBSC产生的富含超氧化物歧化酶/血管内皮生长因子的外切体，并对抗心肌梗死后的病理性重构。
Mesenchymal stem cell therapy improves ischemic heart failure via incompletely understood mechanisms. C1q-TNFα related protein-9 (CTRP9) is a novel anti-oxidative cardiokine capable of improving the local microenvironment and cell survival by its c-terminal active globular domain (gCTRP9). The current study attempted to: 1) identify active gCTRP9 c-terminal polypeptides with stem cell protective function; 2) determine whether a lead polypeptide may enable/enhance cortical bone-derived mesenchymal stem cell (CBSC) cardioprotection against post-myocardial infarction (post-MI) remodeling; and 3) define the responsible underlying cellular/molecular mechanisms. Utilizing I-TASSER structure prediction and 3-D active site modeling, we cloned and purified 3 gCTRP9 fragments (CTRP9-237, CTRP9-277, and CTRP9-281). Their activation of cell salvage kinase was compared against gCTRP9. Among the three fragments, CTRP9-281 (a 45 residue-containing polypeptide) exerted comparable or greater ERK1/2 activation compared to gCTRP9. Treatment with CTRP9-281 or gCTRP9 significantly increased CBSC proliferation and migration, and attenuated oxidative stress-induced CBSC apoptosis. CTRP9-281 and gCTRP9 comparably upregulated SOD2 and SOD3 expression. However, CTRP9-281, not gCTRP9, upregulated FGF2 and VEGFA expression/secretion in an ERK1/2 dependent manner. Administration of gCTRP9 or CTRP9-281 alone attenuated post-MI cardiac dysfunction and improved CBSC retention in the infarcted heart in similar fashion. However, CTRP9-281 exerted greater synergistic effect with CBSC than gCTRP9 related to pro-angiogenic, anti-fibrotic, and anti-remodeling effects. Mechanistically, CTRP9-281 significantly increased SOD2-rich and VEGFA-rich exosome production by CBSC. Exosomes from CTRP9-281 treated CBSC significantly attenuated oxidative stress-induced cardiomyocyte apoptosis in vitro. An exosome generation inhibitor attenuated CTRP9-281 enhancement of CBSC cardioprotection in vivo. We identified a CTRP9 polypeptide that upregulates SOD2/SOD3 expression and improves CBSC survival/retention, similar to gCTRP9. Moreover, CTRP9-281 stimulates VEGFA-rich exosome production by CBSC, exerting superior pro-angiogenic, anti-fibrotic, and cardioprotective actions. CTRP9-281 exerts a comparable effect with gCTRP9 in CBSC anti-oxidant gene expression and promots CBSC survival/retention. CTRP9-281 plays superior synergistic role with CBSC in promoting angiogenesis and anti-fibrosis of ischemic heart. CTRP9-281 significantly enhances SOD-rich/VEGF-rich exosome producted by CBSC, and resists pathological remodeling post-MI.
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影响因子：
20.1
作者：
Cogle CR;Wise E;Meacham AM;Zierold C;Traverse JH;Henry TD;Perin EC;Willerson JT;Ellis SG;Carlson M;Zhao DX;Bolli R;Cooke JP;Anwaruddin S;Bhatnagar A;da Graca Cabreira-Hansen M;Grant MB;Lai D;Moyé L;Ebert RF;Olson RE;Sayre SL;Schulman IH;Bosse RC;Scott EW;Simari RD;Pepine CJ;Taylor DA;Cardiovascular Cell Therapy Research Network (CCTRN)
通讯作者：
Cardiovascular Cell Therapy Research Network (CCTRN)
影响因子：
20.1
作者：
Karantalis V;DiFede DL;Gerstenblith G;Pham S;Symes J;Zambrano JP;Fishman J;Pattany P;McNiece I;Conte J;Schulman S;Wu K;Shah A;Breton E;Davis-Sproul J;Schwarz R;Feigenbaum G;Mushtaq M;Suncion VY;Lardo AC;Borrello I;Mendizabal A;Karas TZ;Byrnes J;Lowery M;Heldman AW;Hare JM
通讯作者：
Hare JM
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
9.5
作者：
Su H;Yuan Y;Wang XM;Lau WB;Wang Y;Wang X;Gao E;Koch WJ;Ma XL
通讯作者：
Ma XL
影响因子：
9.7
作者：
Datta A;Kim H;Lal M;McGee L;Johnson A;Moustafa AA;Jones JC;Mondal D;Ferrer M;Abdel-Mageed AB
通讯作者：
Abdel-Mageed AB