An engineered adipose formulation decreases hepatic inflammation and fibrosis in a rodent model of metabolic dysfunction-associated steatotic liver disease.

IF 4.3 3区 工程技术 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Frontiers in Bioengineering and Biotechnology Pub Date : 2025-06-06 eCollection Date: 2025-01-01 DOI:10.3389/fbioe.2025.1579062
Youngshim Choi, Yinyan Ma, Samson Tom, Alla Danilkovitch, Liqing Yu
{"title":"An engineered adipose formulation decreases hepatic inflammation and fibrosis in a rodent model of metabolic dysfunction-associated steatotic liver disease.","authors":"Youngshim Choi, Yinyan Ma, Samson Tom, Alla Danilkovitch, Liqing Yu","doi":"10.3389/fbioe.2025.1579062","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive stage metabolic dysfunction-associated steatohepatitis (MASH) represent a leading cause of liver-related morbidity and mortality in the U.S. and worldwide. Given the high prevalence and rapid growth of MASLD, the economic and health burden, and MASH-associated morbidity and mortality, there is an unmet medical need for therapies that can stop, slow, or reverse the progression of MASLD. Adipose tissue plays a key role in metabolic health and MASLD pathogenesis through its regulation of energy metabolism and endocrine function. Metabolic dysfunction is often associated with a chronic state of low-grade inflammation in the body including adipose tissue.</p><p><strong>Methods: </strong>In this study, we tested an engineered adipose formulation (AF) composed of a combination of culture-expanded adipose stromal vascular fraction (SVF) cells and adipose tissue particulates in the treatment of MASLD. Human, rat, and mouse AFs (hAF, rAF, and mAF) showed anti-inflammatory activity, which was mediated predominantly by soluble factors present in the adipose particulate. <i>In vivo</i> effects of AFs were evaluated in two rodent models of MASLD: i) obese Zucker rats fed a high-fat, high-cholesterol, and high-fructose diet that mainly manifest hepatic steatosis; and ii) liver-specific CGI-58 knockout mice (LivKO) on a Western diet that display MASH pathologies.</p><p><strong>Results: </strong>Subcutaneous implantation of hAF and rAF in obese Zucker rats significantly reduced hepatic triglycerides. In LivKO mice, mAF reduced hepatic inflammation and fibrosis, though not steatosis, as evidenced by significant decreases in hepatic M1 macrophages and mRNAs for proinflammatory and fibrogenic genes. Immunogenicity testing demonstrated that allogeneic rAF did not induce an immune response, whereas, as anticipated, xenogeneic hAF in rats triggered anti-hAF antibody formation. Despite an immune response against xenogeneic hAF, treatment of rats with hAF ameliorated hepatic steatosis.</p><p><strong>Discussion: </strong>AF has the potential to treat MASH. Future studies focused on the optimization of AF composition, optimal dose and treatment regimen are warranted.</p>","PeriodicalId":12444,"journal":{"name":"Frontiers in Bioengineering and Biotechnology","volume":"13 ","pages":"1579062"},"PeriodicalIF":4.3000,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12179120/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Bioengineering and Biotechnology","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.3389/fbioe.2025.1579062","RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive stage metabolic dysfunction-associated steatohepatitis (MASH) represent a leading cause of liver-related morbidity and mortality in the U.S. and worldwide. Given the high prevalence and rapid growth of MASLD, the economic and health burden, and MASH-associated morbidity and mortality, there is an unmet medical need for therapies that can stop, slow, or reverse the progression of MASLD. Adipose tissue plays a key role in metabolic health and MASLD pathogenesis through its regulation of energy metabolism and endocrine function. Metabolic dysfunction is often associated with a chronic state of low-grade inflammation in the body including adipose tissue.

Methods: In this study, we tested an engineered adipose formulation (AF) composed of a combination of culture-expanded adipose stromal vascular fraction (SVF) cells and adipose tissue particulates in the treatment of MASLD. Human, rat, and mouse AFs (hAF, rAF, and mAF) showed anti-inflammatory activity, which was mediated predominantly by soluble factors present in the adipose particulate. In vivo effects of AFs were evaluated in two rodent models of MASLD: i) obese Zucker rats fed a high-fat, high-cholesterol, and high-fructose diet that mainly manifest hepatic steatosis; and ii) liver-specific CGI-58 knockout mice (LivKO) on a Western diet that display MASH pathologies.

Results: Subcutaneous implantation of hAF and rAF in obese Zucker rats significantly reduced hepatic triglycerides. In LivKO mice, mAF reduced hepatic inflammation and fibrosis, though not steatosis, as evidenced by significant decreases in hepatic M1 macrophages and mRNAs for proinflammatory and fibrogenic genes. Immunogenicity testing demonstrated that allogeneic rAF did not induce an immune response, whereas, as anticipated, xenogeneic hAF in rats triggered anti-hAF antibody formation. Despite an immune response against xenogeneic hAF, treatment of rats with hAF ameliorated hepatic steatosis.

Discussion: AF has the potential to treat MASH. Future studies focused on the optimization of AF composition, optimal dose and treatment regimen are warranted.

一种工程脂肪制剂减少代谢功能障碍相关脂肪性肝病啮齿动物模型中的肝脏炎症和纤维化。
在美国和世界范围内,代谢功能障碍相关脂肪性肝病(MASLD)及其进行性代谢功能障碍相关脂肪性肝炎(MASH)是肝脏相关发病率和死亡率的主要原因。鉴于MASLD的高患病率和快速增长、经济和健康负担以及与MASLD相关的发病率和死亡率,对能够阻止、减缓或逆转MASLD进展的治疗方法的医疗需求尚未得到满足。脂肪组织通过调节能量代谢和内分泌功能,在代谢健康和MASLD发病中起关键作用。代谢功能障碍通常与体内包括脂肪组织的慢性低度炎症状态有关。方法:在这项研究中,我们测试了一种工程脂肪制剂(AF),该制剂由培养扩增的脂肪基质血管组分(SVF)细胞和脂肪组织颗粒组合而成,用于治疗MASLD。人、大鼠和小鼠AFs (hAF、rAF和mAF)显示出抗炎活性,这主要是由脂肪颗粒中的可溶性因子介导的。在两种啮齿类动物模型中评估了AFs的体内作用:i)喂食高脂肪、高胆固醇和高果糖饮食的肥胖Zucker大鼠,主要表现为肝脏脂肪变性;ii)肝脏特异性CGI-58敲除小鼠(LivKO)在西方饮食中表现出MASH病理。结果:肥胖Zucker大鼠皮下植入hAF和rAF可显著降低肝脏甘油三酯。在LivKO小鼠中,mAF减少了肝脏炎症和纤维化,但没有减少脂肪变性,肝脏M1巨噬细胞和促炎和纤维化基因mrna的显著减少证明了这一点。免疫原性测试表明,同种异体rAF不诱导免疫应答,然而,正如预期的那样,大鼠体内的异种hAF触发了抗hAF抗体的形成。尽管对异种hAF有免疫应答,但用hAF治疗大鼠可改善肝脂肪变性。讨论:AF有治疗MASH的潜力。未来的研究将重点放在优化AF的组成、最佳剂量和治疗方案上。
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
Frontiers in Bioengineering and Biotechnology
Frontiers in Bioengineering and Biotechnology Chemical Engineering-Bioengineering
CiteScore
8.30
自引率
5.30%
发文量
2270
审稿时长
12 weeks
期刊介绍: The translation of new discoveries in medicine to clinical routine has never been easy. During the second half of the last century, thanks to the progress in chemistry, biochemistry and pharmacology, we have seen the development and the application of a large number of drugs and devices aimed at the treatment of symptoms, blocking unwanted pathways and, in the case of infectious diseases, fighting the micro-organisms responsible. However, we are facing, today, a dramatic change in the therapeutic approach to pathologies and diseases. Indeed, the challenge of the present and the next decade is to fully restore the physiological status of the diseased organism and to completely regenerate tissue and organs when they are so seriously affected that treatments cannot be limited to the repression of symptoms or to the repair of damage. This is being made possible thanks to the major developments made in basic cell and molecular biology, including stem cell science, growth factor delivery, gene isolation and transfection, the advances in bioengineering and nanotechnology, including development of new biomaterials, biofabrication technologies and use of bioreactors, and the big improvements in diagnostic tools and imaging of cells, tissues and organs. In today`s world, an enhancement of communication between multidisciplinary experts, together with the promotion of joint projects and close collaborations among scientists, engineers, industry people, regulatory agencies and physicians are absolute requirements for the success of any attempt to develop and clinically apply a new biological therapy or an innovative device involving the collective use of biomaterials, cells and/or bioactive molecules. “Frontiers in Bioengineering and Biotechnology” aspires to be a forum for all people involved in the process by bridging the gap too often existing between a discovery in the basic sciences and its clinical application.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信