Senescent Cell-Secreted Netrin-1 Modulates Aging-Related Disorders by Recruiting Sympathetic Fibers.
Senescent Cell-Secreted Netrin-1 Modulates Aging-Related Disorders by Recruiting Sympathetic Fibers.
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衰老细胞分泌的 Netrin-1 通过招募交感纤维来调节衰老相关疾病
DOI：
10.3389/fnagi.2020.507140
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发表时间：
2020
影响因子：
4.8
通讯作者：
Mao ZB
中科院分区：
文献类型：
--
作者：
Yu AQ;Wang J;Zhou XJ;Chen KY;Cao Y;Wang ZX;Mao ZB
细胞衰老与多种衰老相关疾病有关。然而，细胞衰老调节与年龄相关的病理的潜在分子机制在很大程度上仍未被探索。在此，我们报告说，与相应的年轻小鼠组织和人类非病变结肠组织中的交感神经纤维（SF）密度相比，自然衰老的小鼠组织和人类结肠腺瘤组织中的交感神经纤维（SF）密度显着升高。背根神经节（DRG）-人二倍体成纤维细胞共培养测定显示，衰老细胞促进 SF 的生长，表明衰老细胞在体外诱导 SF 的募集。此外，裸鼠皮下移植2BS成纤维细胞显示，移植的衰老2BS成纤维细胞促进SF浸润。关节内注射衰老分子可以降低骨关节炎（OA）中衰老细胞引起的SFs密度并抑制SFs浸润，表明衰老细胞在体内促进衰老组织中SFs的浸润。值得注意的是，SFs水平升高会导致自然衰老小鼠的认知功能受损，这可以通过盐酸普萘洛尔治疗来逆转，盐酸普萘洛尔是一种非选择性β受体阻滞剂，通过阻断非选择性β受体来抑制交感神经活动（SNA）。此外，6-羟基多巴胺 (6-OHDA) 诱导的交感神经切除术通过减少肝脏 SNA，改善了高脂饮食 (HFD) 喂养的 APOE 敲除小鼠（APOE−/− 小鼠）中肝交感神经过度活跃介导的肝脂肪变性。综上所述，这项研究得出的结论是，衰老细胞分泌的 netrin-1 介导 SF 的生长和浸润，从而导致衰老相关疾病，这表明清除衰老细胞或抑制 SNA 是改善交感神经系统 (SNS) 过度活跃引起的衰老相关病理的一种有前景的治疗策略。
Cellular senescence is implicated in several lines of aging-related disorders. However, the potential molecular mechanisms by which cellular senescence modulates age-related pathologies remain largely unexplored. Herein, we report that the density of sympathetic fibers (SFs) is significantly elevated in naturally aged mouse tissues and human colon adenoma tissues compared to the SFs densities in the corresponding young mouse tissues and human non-lesion colon tissues. A dorsal root ganglion (DRG)-human diploid fibroblast coculture assay revealed that senescent cells promote the outgrowth of SFs, indicating that the senescent cells induce recruitment of SFs in vitro. Additionally, subcutaneous transplantation of 2BS fibroblasts in nude mice shows that transplanted senescent 2BS fibroblasts promote SFs infiltration. Intra-articular senolytic molecular injection can reduce SFs density and inhibit SFs infiltration caused by senescent cells in osteoarthritis (OA), suggesting senescent cells promote the infiltration of SFs in vivo in aged tissues. Notably, the elevated level of SFs contributes to impaired cognitive function in naturally aged mice, which can be reversed by treatment with propranolol hydrochloride, a non-selective β receptor blocker that inhibits sympathetic nerve activity (SNA) by blocking non-selective β receptors. Additionally, 6-hydroxydopamine (6-OHDA)-induced sympathectomy improved hepatic sympathetic overactivity mediated hepatic steatosis in high fat diet (HFD)-fed APOE knockout mice (APOE−/− mice) by reducing hepatic SNA. Taken together, this study concludes that senescent cell-secreted netrin-1 mediated SFs outgrowth and infiltration, which contributes to aging-related disorders, suggesting that clearing senescent cells or inhibiting SNA is a promising therapeutic strategy for improving sympathetic nervous system (SNS) hyperactivity-induced aging-related pathologies.
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影响因子：
82.9
作者：
Farr JN;Xu M;Weivoda MM;Monroe DG;Fraser DG;Onken JL;Negley BA;Sfeir JG;Ogrodnik MB;Hachfeld CM;LeBrasseur NK;Drake MT;Pignolo RJ;Pirtskhalava T;Tchkonia T;Oursler MJ;Kirkland JL;Khosla S
通讯作者：
Khosla S
影响因子：
50.3
作者：
Renz BW;Takahashi R;Tanaka T;Macchini M;Hayakawa Y;Dantes Z;Maurer HC;Chen X;Jiang Z;Westphalen CB;Ilmer M;Valenti G;Mohanta SK;Habenicht AJR;Middelhoff M;Chu T;Nagar K;Tailor Y;Casadei R;Di Marco M;Kleespies A;Friedman RA;Remotti H;Reichert M;Worthley DL;Neumann J;Werner J;Iuga AC;Olive KP;Wang TC
通讯作者：
Wang TC
影响因子：
64.8
作者：
Khaminets, Aliaksandr;Heinrich, Theresa;Dikic, Ivan
通讯作者：
Dikic, Ivan
DOI：
10.1016/j.biocel.2019.01.004
发表时间：
2019-03-01
影响因子：
4
作者：
de Lucia, Claudio;Piedepalumbo, Michela;Koch, Walter J.
通讯作者：
Koch, Walter J.
SFRS11 缺失通过调节 LRP8 和 ApoE 导致与衰老相关的认知能力下降
影响因子：
8.8
作者：
Raihan, Obayed;Brishti, Afrina;Liu, Qiang
通讯作者：
Liu, Qiang