Irisin Promotes Cardiac Homing of Intravenously Delivered MSCs and Protects against Ischemic Heart Injury.
Irisin Promotes Cardiac Homing of Intravenously Delivered MSCs and Protects against Ischemic Heart Injury.
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鸢尾素促进静脉输送的 MSC 向心脏归巢并预防缺血性心脏损伤。
DOI：
10.1002/advs.202103697
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Tao L
中科院分区：
文献类型：
--
作者：
Yan W;Chen Y;Guo Y;Xia Y;Li C;Du Y;Lin C;Xu X;Qi T;Fan M;Zhang F;Hu G;Gao E;Liu R;Hai C;Tao L
很少静脉注射间充质基质细胞（MSCs）移植到受损的心肌，从而限制了其治疗缺血性心脏损伤的疗效。在这里，发现鸢尾素预处理增加了通过单次和多次静脉注射给予MI/R小鼠的脂肪组织来源的MSC（ADSC）的心脏归巢超过五倍，随后增加了它们在经历MI/R的大鼠和小鼠中的抗凋亡，促血管生成和抗纤维化作用。RNA测序、京都基因和基因组百科全书（KEGG）信号通路分析和功能丧失研究将CSF 2 RB鉴定为细胞因子受体，其在存在CSF 2的情况下促进鸢尾素处理的ADSC的趋化性，CSF 2是一种在缺血心脏中显著上调的趋化因子。心脏特异性CSF 2敲低阻断了MI/R小鼠静脉注射Irisin处理的ADSC的心脏归巢和心脏保护能力。此外，鸢尾素预处理减少过氧化氢诱导的ADSC的凋亡，并增加ADSC的旁分泌促血管生成作用。ERK 1/2-SOD 2和ERK 1/2-ANGPTL 4分别负责Irisin处理的ADSC的抗凋亡和旁分泌血管生成作用。整合素αV/β5被鉴定为ADSC中的鸢尾素受体。这些结果提供了令人信服的证据表明，鸢尾素预处理可以是一种有效的手段，以优化静脉内输送的MSC作为缺血性心脏损伤的治疗。鸢尾素通过与整合素αV/β5结合激活ADSC中的ERK 1/2，并增加CSF 2 RB、SOD 2和ANGPTL 4表达。缺血心脏释放趋化因子CSF 2并形成CSF 2梯度。CSF 2 RB响应CSF 2梯度并促进ADSC的心脏归巢。SOD 2减少ADSC凋亡。ANGPTL 4从ADSC释放并有助于ADSC的旁分泌促血管生成作用。
Few intravenously administered mesenchymal stromal cells (MSCs) engraft to the injured myocardium, thereby limiting their therapeutic efficacy for the treatment of ischemic heart injury. Here, it is found that irisin pretreatment increases the cardiac homing of adipose tissue‐derived MSCs (ADSCs) administered by single and multiple intravenous injections to mice with MI/R by more than fivefold, which subsequently increases their antiapoptotic, proangiogenic, and antifibrotic effects in rats and mice that underwent MI/R. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis, and loss‐of‐function studies identified CSF2RB as a cytokine receptor that facilitates the chemotaxis of irisin‐treated ADSCs in the presence of CSF2, a chemokine that is significantly upregulated in the ischemic heart. Cardiac‐specific CSF2 knockdown blocked the cardiac homing and cardioprotection abilities of intravenously injected irisin‐treated ADSCs in mice subjected to MI/R. Moreover, irisin pretreatment reduced the apoptosis of hydrogen peroxide‐induced ADSCs and increased the paracrine proangiogenic effect of ADSCs. ERK1/2‐SOD2, and ERK1/2‐ANGPTL4 are responsible for the antiapoptotic and paracrine angiogenic effects of irisin‐treated ADSCs, respectively. Integrin αV/β5 is identified as the irisin receptor in ADSCs. These results provide compelling evidence that irisin pretreatment can be an effective means to optimize intravenously delivered MSCs as therapy for ischemic heart injury. Irisin activates ERK1/2 in ADSCs by binding to integrin αV/β5, and increases CSF2RB, SOD2, and ANGPTL4 expression. The ischemic heart releases the chemokine CSF2 and forms a CSF2 gradient. CSF2RB responds to the CSF2 gradient and promotes the cardiac homing of ADSCs. SOD2 reduces ADSC apoptosis. ANGPTL4 is released from ADSCs and contributes to the paracrine proangiogenic effect of ADSCs.
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影响因子：
9.8
作者：
Anastasilakis, Athanasios D.;Koulaxis, Dimitrios;Mantzoros, Christos S.
通讯作者：
Mantzoros, Christos S.
影响因子：
8
作者：
Cho, Dong Im;Kong, Hye-jin;Ahn, Youngkeun
通讯作者：
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影响因子：
17.1
作者：
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影响因子：
20.1
作者：
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通讯作者：
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影响因子：
39.3
作者：
Piepoli, Massimo F.;Corra, Ugo;Schmid, Jean-Paul
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