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CAR-T细胞可用于逆转衰老相关的疾病
2020-06-20 16:29

美国纪念斯隆凯特林肿瘤研究所Scott W. Lowe、Michel Sadelain等研究人员合作开发出抗衰老CAR-T细胞用于逆转衰老相关的疾病。相关论文于2020年6月17日在线发表在《自然》杂志上。

研究人员测试了靶向衰老细胞的嵌合抗原受体(CAR)T细胞,其可作为有效的抗衰老治疗剂。研究人员将尿激酶型纤溶酶原激活物受体(uPAR)鉴定为在衰老过程中被广泛诱导的细胞表面蛋白,并显示uPAR特异性CAR T细胞在体外和体内均能有效消除衰老细胞。靶向uPAR的CAR T细胞延长了用诱导衰老药物治疗的肺腺癌小鼠存活率,并恢复了化学或通过饮食诱发肝纤维化小鼠体内的组织稳态。这些结果建立了衰老相关疾病CAR T细胞的治疗潜力。

据了解,细胞衰老的特征是稳定的细胞周期停滞以及一个调节组织微环境的分泌程序。从生理学上讲,衰老是一种肿瘤抑制机制,可防止癌前细胞的扩增,并在伤口愈合反应中发挥有益作用。病理上,衰老细胞的异常积累会产生炎症环境,从而导致慢性组织损伤,并导致诸如肝和肺纤维化、动脉粥样硬化、糖尿病和骨关节炎等疾病。因此,消除小鼠受损组织中的衰老细胞可改善这些病理症状,甚至可延长寿命。

附:英文原文

Title: Senolytic CAR T cells reverse senescence-associated pathologies

Author: Corina Amor, Judith Feucht, Josef Leibold, Yu-Jui Ho, Changyu Zhu, Direna Alonso-Curbelo, Jorge Mansilla-Soto, Jacob A. Boyer, Xiang Li, Theodoros Giavridis, Amanda Kulick, Shauna Houlihan, Ellinor Peerschke, Scott L. Friedman, Vladimir Ponomarev, Alessandra Piersigilli, Michel Sadelain, Scott W. Lowe

Issue&Volume: 2020-06-17

Abstract: Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity1,2,8,9,10. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.

DOI: 10.1038/s41586-020-2403-9

Source: https://www.nature.com/articles/s41586-020-2403-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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