Evolocumab protects mice from radiation-induced damage by affecting hematopoietic cell lineage

IF 3.6 2区生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Genomics Pub Date : 2026-07-01 Epub Date: 2026-06-13 DOI:10.1016/j.ygeno.2026.111277

Yuhan Gan, Jiawei Zhou, Bendong Li, Daqian Huang, Yuejun Ma, Lu Pei, Kaiwen Sheng, Liao Zhang, Ying Cheng, Jicong Du, Shengyun Cai, Cong Liu

{"title":"Evolocumab protects mice from radiation-induced damage by affecting hematopoietic cell lineage","authors":"Yuhan Gan, Jiawei Zhou, Bendong Li, Daqian Huang, Yuejun Ma, Lu Pei, Kaiwen Sheng, Liao Zhang, Ying Cheng, Jicong Du, Shengyun Cai, Cong Liu","doi":"10.1016/j.ygeno.2026.111277","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>The hematopoietic system is extremely sensitive to ionizing radiation(IR) and is easily damaged after exposure. Recent studies [1, 2] have shown that hematopoietic lineage differentiation may play a key role in Ionizing radiation -induced acute injury.</div></div><div><h3>Methods</h3><div>C57BL/6 mice matched for age, sex and weight were randomly grouped and intraperitoneal injected with PBS, Evolocumab (80.0 mg/kg) or MMP9-IN (20.0 mg/kg). Survival time, body weight, pathology, hematopoietic cell differentiation changes and organoids of the mice after IR (10.0 Gy) were compared, and the mechanism of action in tissues was verified by transcriptome sequencing.</div></div><div><h3>Results</h3><div>Ionizing radiation can inhibit hematopoietic cell lineage differentiation and affect cholesterol metabolism. The expression of the <em>Pcsk9</em> gene was significantly upregulated after IR. Treatment with a <em>Pcsk9</em> monoclonal antibody (Evolocumab) exerted significant radioprotective effects, including improving the survival rate of irradiated mice, reducing body weight loss, preserving the integrity of the bone marrow cavity, and promoting cellular proliferation. Flow cytometric analysis showed that Evolocumab significantly increased hematopoietic precursor cells and hematopoietic stem cells and promoted their differentiation into ST-LSKs and MPPs. In addition, the proportions of CMPs and GMPs were increased, whereas the proportion of MEPs was decreased. RNA sequencing results suggested that the IR-induced downregulation of <em>Cd3e</em> within the hematopoietic cell lineage pathway could be rescued by Evolocumab, which was further validated at the cellular level. CD3e is a T-cell-associated marker, and Evolocumab treatment was associated with an increased proportion of CD3e<sup>+</sup> T cells. Analysis of previously reported hematopoiesis-related factors [3–5] indicated that Evolocumab markedly upregulated <em>Mmp9</em> expression. Correlation analysis revealed that <em>Pcsk9</em> was negatively correlated with <em>Cd3e</em>, whereas <em>Cd3e</em> was positively correlated with <em>Mmp9</em>. Following ionizing radiation, <em>Mmp9</em> knockout (<em>Mmp9</em> KO) mice exhibited reduced survival compared with wild-type mice. Moreover, in wild-type mice, administration of an MMP9 inhibitor (MMP9-IN) attenuated the radioprotective effects of Evolocumab, indicating that <em>Mmp9</em> contributes to Evolocumab-mediated radioprotection.</div></div><div><h3>Conclusion</h3><div>Evolocumab exerts a positive effect on promoting the proliferation and differentiation of hematopoietic stem cells against IR-induced hematopoietic system injury, with its protective mechanism likely involving the activation of hematopoietic cell lineages to upregulate CD3e<sup>+</sup> T cells and Mmp9 expression.</div></div>","PeriodicalId":12521,"journal":{"name":"Genomics","volume":"118 4","pages":"Article 111277"},"PeriodicalIF":3.6000,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genomics","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0888754326000856","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/6/13 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

The hematopoietic system is extremely sensitive to ionizing radiation(IR) and is easily damaged after exposure. Recent studies [1, 2] have shown that hematopoietic lineage differentiation may play a key role in Ionizing radiation -induced acute injury.

Methods

C57BL/6 mice matched for age, sex and weight were randomly grouped and intraperitoneal injected with PBS, Evolocumab (80.0 mg/kg) or MMP9-IN (20.0 mg/kg). Survival time, body weight, pathology, hematopoietic cell differentiation changes and organoids of the mice after IR (10.0 Gy) were compared, and the mechanism of action in tissues was verified by transcriptome sequencing.

Results

Ionizing radiation can inhibit hematopoietic cell lineage differentiation and affect cholesterol metabolism. The expression of the Pcsk9 gene was significantly upregulated after IR. Treatment with a Pcsk9 monoclonal antibody (Evolocumab) exerted significant radioprotective effects, including improving the survival rate of irradiated mice, reducing body weight loss, preserving the integrity of the bone marrow cavity, and promoting cellular proliferation. Flow cytometric analysis showed that Evolocumab significantly increased hematopoietic precursor cells and hematopoietic stem cells and promoted their differentiation into ST-LSKs and MPPs. In addition, the proportions of CMPs and GMPs were increased, whereas the proportion of MEPs was decreased. RNA sequencing results suggested that the IR-induced downregulation of Cd3e within the hematopoietic cell lineage pathway could be rescued by Evolocumab, which was further validated at the cellular level. CD3e is a T-cell-associated marker, and Evolocumab treatment was associated with an increased proportion of CD3e⁺ T cells. Analysis of previously reported hematopoiesis-related factors [3–5] indicated that Evolocumab markedly upregulated Mmp9 expression. Correlation analysis revealed that Pcsk9 was negatively correlated with Cd3e, whereas Cd3e was positively correlated with Mmp9. Following ionizing radiation, Mmp9 knockout (Mmp9 KO) mice exhibited reduced survival compared with wild-type mice. Moreover, in wild-type mice, administration of an MMP9 inhibitor (MMP9-IN) attenuated the radioprotective effects of Evolocumab, indicating that Mmp9 contributes to Evolocumab-mediated radioprotection.

Conclusion

Evolocumab exerts a positive effect on promoting the proliferation and differentiation of hematopoietic stem cells against IR-induced hematopoietic system injury, with its protective mechanism likely involving the activation of hematopoietic cell lineages to upregulate CD3e⁺ T cells and Mmp9 expression.

查看原文本刊更多论文

Evolocumab通过影响造血细胞谱系来保护小鼠免受辐射诱导的损伤。

背景：造血系统对电离辐射（IR）非常敏感，暴露后容易损伤。最近的研究[1,2]表明，造血谱系分化可能在电离辐射引起的急性损伤中起关键作用。方法：将年龄、性别、体重匹配的C57BL/6小鼠随机分组，分别腹腔注射PBS、Evolocumab（80.0 mg/kg）或MMP9-IN（20.0 mg/kg）。比较IR（10.0 Gy）后小鼠的生存时间、体重、病理、造血细胞分化变化和类器官，并通过转录组测序验证其在组织中的作用机制。结果：电离辐射可抑制造血细胞谱系分化，影响胆固醇代谢。IR后Pcsk9基因的表达显著上调。使用Pcsk9单克隆抗体（Evolocumab）治疗具有显著的放射防护作用，包括提高照射小鼠的存活率，减轻体重减轻，保持骨髓腔的完整性，促进细胞增殖。流式细胞分析显示，Evolocumab显著增加造血前体细胞和造血干细胞，促进其向st - lsk和MPPs分化。此外，cmp和gmp的比例增加，而MEPs的比例下降。RNA测序结果提示，Evolocumab可以挽救ir诱导的造血细胞谱系通路内Cd3e的下调，并在细胞水平上进一步验证。CD3e是一种T细胞相关标志物，Evolocumab治疗与CD3e+ T细胞比例增加相关。对先前报道的造血相关因子的分析[3-5]表明，Evolocumab可显著上调Mmp9的表达。相关分析显示Pcsk9与Cd3e呈负相关，而Cd3e与Mmp9呈正相关。电离辐射后，与野生型小鼠相比，Mmp9敲除（Mmp9 KO）小鼠的存活率降低。此外，在野生型小鼠中，给药MMP9抑制剂（MMP9- in）减弱了Evolocumab的放射保护作用，表明MMP9有助于Evolocumab介导的放射保护。结论：Evolocumab对ir诱导的造血系统损伤具有促进造血干细胞增殖和分化的积极作用，其保护机制可能与激活造血细胞系上调CD3e+ T细胞和Mmp9表达有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Genomics 生物-生物工程与应用微生物

CiteScore

9.60

自引率

2.30%

发文量

260

审稿时长

60 days

期刊介绍： Genomics is a forum for describing the development of genome-scale technologies and their application to all areas of biological investigation. As a journal that has evolved with the field that carries its name, Genomics focuses on the development and application of cutting-edge methods, addressing fundamental questions with potential interest to a wide audience. Our aim is to publish the highest quality research and to provide authors with rapid, fair and accurate review and publication of manuscripts falling within our scope.