Senescent Cell-Secreted Netrin-1 Modulates Aging-Related Disorders by Recruiting Sympathetic Fibers
| Autor: | Ai Qing Yu, Jie Wang, Xiao Jia Zhou, Ke Yu Chen, You De Cao, Zhi Xiao Wang, Ze Bin Mao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases Aging Sympathetic nervous system Cognitive Neuroscience lcsh:RC321-571 03 medical and health sciences 0302 clinical medicine fluids and secretions Dorsal root ganglion Netrin medicine aged tissues aging-related disorders Fibroblast Senolytic lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Original Research senescent cells Chemistry medicine.disease Cell biology Transplantation 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Knockout mouse sympathetic fibers netrin-1 Infiltration (medical) Neuroscience |
| Zdroj: | Frontiers in Aging Neuroscience, Vol 12 (2020) Frontiers in Aging Neuroscience |
| ISSN: | 1663-4365 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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