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鱼鳔来源的细胞外基质水凝胶通过免疫调节和血管生成有效治疗心肌缺血损伤。

Fish Swim Bladder-Derived ECM Hydrogels Effectively Treat Myocardial Ischemic Injury through Immunomodulation and Angiogenesis.

作者信息

Fu Yulong, Gao Canran, Zhang Hailing, Liu Jing, Li Boxuan, Chen Wei, Chen Xiuping, Lin Xue, Fang Ligang, Wang Zhihong

机构信息

Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, 300071, China.

Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.

出版信息

Adv Sci (Weinh). 2025 Jun;12(23):e2500036. doi: 10.1002/advs.202500036. Epub 2025 Apr 9.

Abstract

Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure.

摘要

可注射水凝胶植入物是治疗缺血性心力衰竭的一种有前景的治疗方法;但其疗效往往受到生物活性低、耐久性差和注射技术不完善的限制。在此,开发了一种独特的水凝胶,其包含来自鱼鳔的细胞外基质(FSB-ECM),与哺乳动物来源的ECM相比具有明显优势,如低抗原性、生物活性和来源安全性。它由胶原蛋白、糖蛋白和蛋白聚糖组成,包括心肌基质中常见的13种蛋白质以及三种特定蛋白质:硫酸乙酰肝素蛋白聚糖、胶原蛋白12α1和血管性血友病因子。这种水凝胶增强心肌细胞黏附和伸展,同时促进血管生成和M2巨噬细胞极化。此外,其储能模量(G')随时间增加,5分钟后达到约1000帕,这有利于经导管递送和原位凝胶化。此外,这种水凝胶为心脏收缩提供持续支持,具有卓越的持久性。在缺血性心力衰竭大鼠模型中,FSB-ECM治疗可显著提高射血分数,同时伴有血管生成增加、炎症减轻和梗死面积减小。最后,RNA测序结合体外试验确定血管生成素样蛋白4是介导FSB-ECM治疗效果的关键蛋白。总体而言,这种基于FSB-ECM的新型可注射水凝胶适用于经导管递送,对治疗心力衰竭具有显著的修复能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ddf7/12199318/cd5fadfd095b/ADVS-12-2500036-g004.jpg

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