Augmentation of Bone Regeneration by Depletion of Stress-Induced Senescent Cells Using Catechin and Senolytics
Augmentation of Bone Regeneration by Depletion of Stress-Induced Senescent Cells Using Catechin and Senolytics
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DOI：
10.3390/ijms21124213
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发表时间：
2020-06-01
影响因子：
5.6
通讯作者：
Umeda, Makoto
中科院分区：
文献类型：
--
作者：
Honda, Yoshitomo;Huang, Anqi;Umeda, Makoto
尽管骨再生医学取得了进展，但应激诱导的细胞早衰与骨再生之间的关系仍然很大程度上是未知的。在这里，我们证明了植入脂多糖(LPS)缓释明胶海绵(LS-G)增加了SIPS细胞的数量，并且这些细胞的消除促进了大鼠颅骨临界大小的骨缺损中的骨形成。组织学(苏木精-伊红和SA-β-GAL)和免疫组织学(p16和p21用于分析细胞衰老，4-HNE用于氧化)染色用于鉴定SIPS细胞并阐明其可能的机制。分别在术后1周和4周用微型计算机断层扫描分析缺损区的骨形成情况。在LS-G植入的同时，局部给予表没食子儿茶素没食子酸酯(EGCG)和全身给药(达沙替尼和槲皮素：d+q)以消除SIPS细胞。LS-G植入后，SA-β-Gal-、p16-和p21阳性细胞(SIPs细胞)聚集在缺损区。而LS-G+EGCG组和LS-G+D+Q组较LS-G组的SiPS细胞数量少，新生骨增多。我们证明，内毒素持续刺激诱导的SIPs细胞在骨形成过程中可能起到有害的作用。控制这些细胞的数量是促进骨再生的一个很有前途的策略。
Despite advances in bone regenerative medicine, the relationship between stress-induced premature senescence (SIPS) in cells and bone regeneration remains largely unknown. Herein, we demonstrated that the implantation of a lipopolysaccharide (LPS) sustained-release gelatin sponge (LS-G) increases the number of SIPS cells and that the elimination of these cells promotes bone formation in critical-sized bone defects in the rat calvaria. Histological (hematoxylin-eosin and SA-beta-gal) and immunohistological (p16 and p21 for analyzing cellular senescence and 4-HNE for oxidation) staining was used to identify SIPS cells and elucidate the underlying mechanism. Bone formation in defects were analyzed using microcomputed tomography, one and four weeks after surgery. Parallel to LS-G implantation, local epigallocatechin gallate (EGCG) administration, and systemic senolytic (dasatinib and quercetin: D+Q) administration were used to eliminate SIPS cells. After LS-G implantation, SA-beta-gal-, p16-, and p21-positive cells (SIPS cells) accumulated in the defects. However, treatment with LS-G+EGCG and LS-G+D+Q resulted in lower numbers of SIPS cells than that with LS-G in the defects, resulting in an augmentation of newly formed bone. We demonstrated that SIPS cells induced by sustained stimulation by LPS may play a deleterious role in bone formation. Controlling these cell numbers is a promising strategy to increase bone regeneration.