Time-resolved transcriptomic profiling of senescence-associated secretory phenotype (SASP) in multiple senescent cell subtypes
Time-resolved transcriptomic profiling of senescence-associated secretory phenotype (SASP) in multiple senescent cell subtypes
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DOI：
10.1101/2022.06.27.497690
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发表时间：
2022-06
期刊：
影响因子：
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通讯作者：
N. Razali;Y. Moriyama;Yatzu Chiu;Kojiro Suda;Keiko Kono
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文献类型：
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作者：
N. Razali;Y. Moriyama;Yatzu Chiu;Kojiro Suda;Keiko Kono
细胞衰老是一种不可逆的细胞周期阻滞，由多种触发因素引起，包括端粒缩短、癌基因激活和DNA损伤。衰老细胞表现出衰老相关分泌表型（SASP），这是一种导致机体衰老的病理特征。我们之前的研究表明，瞬态质膜损伤（PMD）诱导了一种新的细胞衰老亚型（PMDS），并伴有SASP，但在PMDS诱导过程中SASP的总体表达谱尚不清楚。在这里，我们利用mRNA-seq、qPCR和生物信息学，揭示了PMDS中SASP的时间分辨转录组谱，并将其与钙流诱导的衰老、DNA损伤反应诱导的衰老和复制性衰老进行了比较。尽管SASP因子的表达在衰老过程中稳步增加，但我们发现SASP的变化在早期PMDS中达到峰值。通路对比分析和Ingenuity pathway Analysis提示，在PMDS早期，伤口愈合的SASP因子Il-6、Mmp1和Mmp3抑制GPVI胶原信号通路，而GPVI胶原信号通路又进一步上调相同的SASP因子，形成一个反馈回路。在衰老晚期，包括Il-6和Ccl2在内的常见SASP因子在所有衰老细胞亚型中均上调。因此，SASP在衰老早期是多样化的，而在衰老晚期变得相对均匀。不同的SASP可能参与体内衰老细胞亚型特异性旁分泌/自分泌功能。
Cellular senescence, irreversible cell cycle arrest, is induced by various triggers including telomere shortening, oncogene activation, and DNA damage. Senescent cells exhibit the senescence-associated secretory phenotype (SASP), a pathological feature that contributes to organismal aging. We previously showed that transient plasma membrane damage (PMD) induces a novel subtype of cellular senescence (PMDS) accompanied by SASP, but the overall expression profiles of SASP during PMDS induction was unknown. Here, using mRNA-seq, qPCR, and bioinformatics, we revealed the time-resolved SASP transcriptomic profile in PMDS in comparison with calcium influx-induced senescence, DNA damage response-induced senescence, and replicative senescence. Although the expression of SASP factors was postulated to increase steadily during senescence, we counterintuitively found that the variety of SASP peaks in early PMDS. The pathway comparison analyses and Ingenuity Pathway Analysis suggest that, in early PMDS, wound-healing SASP factors, namely Il-6, Mmp1, and Mmp3, inhibit the GPVI collagen signaling pathway, which in turn further upregulates the same SASP factors, forming a feedback loop. At late senescence, common SASP factors including Il-6 and Ccl2 are upregulated in all senescent cell subtypes. Thus, SASP is diverse at early senescence and becomes relatively uniform at late senescence. Diverse SASP may contribute to senescent cell subtype-specific paracrine/autocrine functions in vivo.