Spatial FAP Expression as Detected by ⁶⁸ Ga-FAPI-46 Identifies Myofibroblasts Beyond the Infarct Scar After Reperfusion.

IF 2.5 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2025-04-01 Epub Date: 2025-03-03 DOI:10.1007/s11307-025-01994-6

Annika Hess, Alexandra Renko, Andreas Schäfer, Mira Jung, Daniela Fraccarollo, Jan D Schmitto, Johanna Diekmann, Thomas Thum, Frank M Bengel, Johann Bauersachs, James T Thackeray, Jochen Tillmanns

{"title":"Spatial FAP Expression as Detected by 68 Ga-FAPI-46 Identifies Myofibroblasts Beyond the Infarct Scar After Reperfusion.","authors":"Annika Hess, Alexandra Renko, Andreas Schäfer, Mira Jung, Daniela Fraccarollo, Jan D Schmitto, Johanna Diekmann, Thomas Thum, Frank M Bengel, Johann Bauersachs, James T Thackeray, Jochen Tillmanns","doi":"10.1007/s11307-025-01994-6","DOIUrl":null,"url":null,"abstract":"Purpose: Myocardial infarction (MI) triggers complex cellular responses essential for tissue repair and remodeling, including myofibroblast activation. Fibroblast activation protein alpha (FAP) identifies activated myofibroblasts post-MI, however its spatial distribution relative to the scar and area at risk (AAR) is unclear. Non-invasive FAP-imaging with PET radiotracer 68 Ga-FAPI-46 shows uptake beyond the infarct scar. We therefore aimed to characterize FAP expression in the AAR using a myocardial ischemia-reperfusion (MI/R) model in mice.Procedures: We induced MI/R in male C57BL/6N mice. The AAR was identified by in vivo lectin staining, and expression of FAP, CD68, and hypoxic tissues were measured using immunohistochemistry. Spatial FAP was further interrogated by 68 Ga-FAPI-46 in mice by autoradiography and humans by PET. Additionally, human cardiac tissues from acute MI patients were examined for fibroblasts and inflammatory cells by expression of FAP, CD13, and α-smooth muscle actin.Results: FAP expression peaked three days post-MI/R predominantly within the AAR (p < 0.05 vs. d0). Consistent between murine models and human tissues, FAP+ myofibroblasts accumulated within the infarct scar and borderzone, occasionally extending into non-ischemic myocardium. CD68+ macrophages peaked similarly at three days post-MI/R (p < 0.05 vs. d0). FAP expression weakly correlated with CD68 but not with extent of ischemic or hypoxic territory post-MI/R. FAP imaging in mice and humans revealed aligned non-uniform 68 Ga-FAPI-46 uptake extending from the infarct scar into surviving myocardium after MI.Conclusions: Our findings demonstrate a distinct FAP expression pattern post-MI/R. The alignment of ex vivo 68 Ga-FAPI-46 signal with myofibroblasts in the AAR supports its identification of a unique substrate in myocardial injury complementing other non-invasive imaging measurements of perfusion, viability and fibrosis.","PeriodicalId":18760,"journal":{"name":"Molecular Imaging and Biology","volume":" ","pages":"173-183"},"PeriodicalIF":2.5000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062164/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Imaging and Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11307-025-01994-6","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/3 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: Myocardial infarction (MI) triggers complex cellular responses essential for tissue repair and remodeling, including myofibroblast activation. Fibroblast activation protein alpha (FAP) identifies activated myofibroblasts post-MI, however its spatial distribution relative to the scar and area at risk (AAR) is unclear. Non-invasive FAP-imaging with PET radiotracer ⁶⁸ Ga-FAPI-46 shows uptake beyond the infarct scar. We therefore aimed to characterize FAP expression in the AAR using a myocardial ischemia-reperfusion (MI/R) model in mice.

Procedures: We induced MI/R in male C57BL/6N mice. The AAR was identified by in vivo lectin staining, and expression of FAP, CD68, and hypoxic tissues were measured using immunohistochemistry. Spatial FAP was further interrogated by ⁶⁸ Ga-FAPI-46 in mice by autoradiography and humans by PET. Additionally, human cardiac tissues from acute MI patients were examined for fibroblasts and inflammatory cells by expression of FAP, CD13, and α-smooth muscle actin.

Results: FAP expression peaked three days post-MI/R predominantly within the AAR (p < 0.05 vs. d0). Consistent between murine models and human tissues, FAP⁺ myofibroblasts accumulated within the infarct scar and borderzone, occasionally extending into non-ischemic myocardium. CD68⁺ macrophages peaked similarly at three days post-MI/R (p < 0.05 vs. d0). FAP expression weakly correlated with CD68 but not with extent of ischemic or hypoxic territory post-MI/R. FAP imaging in mice and humans revealed aligned non-uniform ⁶⁸ Ga-FAPI-46 uptake extending from the infarct scar into surviving myocardium after MI.

Conclusions: Our findings demonstrate a distinct FAP expression pattern post-MI/R. The alignment of ex vivo ⁶⁸ Ga-FAPI-46 signal with myofibroblasts in the AAR supports its identification of a unique substrate in myocardial injury complementing other non-invasive imaging measurements of perfusion, viability and fibrosis.

查看原文本刊更多论文

68 Ga-FAPI-46检测再灌注后梗死瘢痕外肌成纤维细胞的空间FAP表达

目的：心肌梗死（MI）触发复杂的细胞反应，对组织修复和重塑至关重要，包括肌成纤维细胞激活。成纤维细胞活化蛋白α (FAP)识别心肌梗死后活化的肌成纤维细胞，但其相对于疤痕和危险区域（AAR）的空间分布尚不清楚。PET示踪剂68ga - fapi -46的无创fap成像显示梗死疤痕以外的摄取。因此，我们旨在通过小鼠心肌缺血-再灌注（MI/R）模型来表征FAP在AAR中的表达。方法：对C57BL/6N雄性小鼠进行MI/R诱导。采用体内凝集素染色法鉴定AAR，免疫组化法检测FAP、CD68和缺氧组织的表达。68 Ga-FAPI-46分别通过放射自显影和PET检测小鼠和人的空间FAP。此外，通过FAP、CD13和α-平滑肌肌动蛋白的表达检测急性心肌梗死患者心肌组织的成纤维细胞和炎症细胞。结果：心肌梗死/心肌梗死后3天，FAP表达达到高峰，主要集中在梗死疤痕和交界区积聚的AAR (p) +肌成纤维细胞内，偶尔延伸到非缺血心肌。CD68+巨噬细胞在mi /R后3天达到相似的峰值（p 68）， Ga-FAPI-46摄取从梗死疤痕延伸到mi后存活的心肌。结论：我们的研究结果表明mi /R后FAP表达模式不同。离体68ga - fapi -46信号与肌成纤维细胞在AAR中的一致性支持其识别心肌损伤的独特底物，补充了灌注，活力和纤维化的其他非侵入性成像测量。

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

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.