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Zeb2os Hinders Cardiac Healing by Suppressing ZEB2 Reactivation and Cardiomyocyte Dedifferentiation. 通过抑制ZEB2再激活和心肌细胞去分化阻碍心脏愈合。
IF 20.1 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-29 DOI: 10.1161/circresaha.125.327212
Rocco Caliandro,Merel L Ligtermoet,Alexandra E Giovou,Azra Husetić,Arie R Boender,Huiling Zhou,Jermo Hanemaaijer-van der Veer,Liangyu Hu,Deli Zhang,Lorena Zentilin,Roelof-Jan Oostra,Gerard J J Boink,Mauro Giacca,Vincent M Christoffels,Monika M Gladka
BACKGROUNDLong noncoding RNAs have emerged as critical regulators in cardiovascular biology, influencing cardiac development, remodeling, and regeneration. Zeb2os, a natural antisense transcript of the Zeb2 gene, has been linked to these processes in various organs. Although ZEB2 (zinc finger E-box-binding homeobox 2) promotes cardiac repair, the role of Zeb2os in these processes remains unclear. This study investigates the role of Zeb2os in modulating ZEB2 expression and cardiac remodeling after ischemic injury.METHODSWe used adeno-associated virus vectors to overexpress Zeb2os in mouse models of cardiac IR injury. RNA sequencing, immunofluorescence, and high-resolution respirometry were used to evaluate the effects of Zeb2os delivery on gene expression, ZEB2 reactivation, cardiomyocyte phenotype, scar composition, and mitochondrial function. Experiments in cultured cardiomyocytes under hypoxia further explored the regulatory dynamics between Zeb2os and Zeb2.RESULTSWe identified Zeb2os as a hypoxia-responsive long noncoding RNA that displays an inverse and oscillatory expression pattern with Zeb2 in both in vitro and in vivo models of cardiac injury. Functional experiments revealed that Zeb2os negatively regulates ZEB2 expression, impairing the cardiomyocyte dedifferentiation and metabolic remodeling necessary for effective repair. Adeno-associated virus-mediated delivery of Zeb2os resulted in preserved sarcomere structure, altered scar composition, reduced expression of regenerative genes, and diminished cardiac function following injury. In contrast, silencing of Zeb2os increased ZEB2 protein expression, suggesting a potential therapeutic strategy to enhance repair. Mechanistically, modulation of Zeb2os levels inversely regulated ZEB2 protein expression, whereas ZEB2 modulation did not affect Zeb2os levels, indicating a unidirectional regulatory axis between the 2 transcripts.CONCLUSIONSOur findings identify Zeb2os as a stress-responsive inhibitor of ZEB2 reactivation that limits cardiomyocyte plasticity and hinders repair following ischemic injury. Given its specific activity under ischemic conditions, targeting Zeb2os may represent a novel therapeutic strategy to enhance endogenous cardiac regeneration.
长链非编码rna已成为心血管生物学中重要的调节因子,影响心脏发育、重塑和再生。Zeb2os是Zeb2基因的天然反义转录物,与多种器官的这些过程有关。虽然ZEB2(锌指E-box-binding homeobox 2)促进心脏修复,但zeb20s在这些过程中的作用尚不清楚。本研究探讨了Zeb2os在缺血性损伤后调节ZEB2表达和心脏重构中的作用。方法采用腺相关病毒载体在小鼠心脏IR损伤模型中过表达zeb2o。采用RNA测序、免疫荧光和高分辨率呼吸测定法来评估Zeb2os递送对基因表达、ZEB2再激活、心肌细胞表型、疤痕组成和线粒体功能的影响。缺氧培养心肌细胞实验进一步探讨了Zeb2os和Zeb2之间的调控动态。结果:在体外和体内心脏损伤模型中,我们发现Zeb2os是一种缺氧反应的长链非编码RNA,与Zeb2表现出反向和振荡的表达模式。功能实验显示,Zeb2os负调控ZEB2表达,损害有效修复所必需的心肌细胞去分化和代谢重塑。腺相关病毒介导的Zeb2os递送导致损伤后肌节结构保留,疤痕成分改变,再生基因表达减少,心功能减弱。相反,沉默Zeb2os会增加ZEB2蛋白的表达,这提示了一种潜在的增强修复的治疗策略。从机制上讲,Zeb2os水平的调节反向调节ZEB2蛋白的表达,而ZEB2的调节不影响Zeb2os水平,这表明2个转录本之间存在单向调节轴。结论Zeb2os是一种应激反应性的ZEB2再激活抑制剂,限制了心肌细胞的可塑性,阻碍了缺血损伤后的修复。鉴于其在缺血条件下的特异性活性,靶向Zeb2os可能是一种新的治疗策略,可以增强内源性心脏再生。
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引用次数: 0
When Smell Drives Swell: Olfr2 Fuels Inflammation in AAA. 当气味驱动膨胀:Olfr2刺激AAA发炎。
IF 20.1 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-29 DOI: 10.1161/circresaha.125.327969
Gage M Stuttgen,Michael Chang,Jesse W Williams
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引用次数: 0
Recruited and Resident Macrophages Play a Distinct Role in Vascular Remodeling in Pulmonary Arterial Hypertension. 招募和常驻巨噬细胞在肺动脉高压血管重构中发挥着独特的作用。
IF 20.1 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-29 DOI: 10.1161/circresaha.125.328023
Megha Talati,James West
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引用次数: 0
Glucose Metabolic Enzyme PFKFB3 in Cardiopulmonary Vascular Health and Disease. 葡萄糖代谢酶PFKFB3在心肺血管健康和疾病中的作用。
IF 20.1 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-29 DOI: 10.1161/circresaha.125.327074
Yingzi Li,Joseph Loscalzo,Wusheng Xiao
Cardiopulmonary vascular diseases are the leading cause of death worldwide. Metabolic reprogramming and inflammation are 2 commonly shared hallmarks of such diseases. The bifunctional enzymes PFKFB (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases) 1 to 4 are well-known for their critical functions in glucose metabolism. Emerging evidence has indicated that PFKFB enzymes, particularly PFKFB3, are essential immunometabolic regulators and implicated in cardiopulmonary vascular and other pathologies. We here first summarize the structural basis for the catalytic function of PFKFB family enzymes, introduce the recent advances on the regulation of PFKFB3 expression and activity as well as its nonmetabolic functions, then elaborate on how dysregulation of PFKFBs influences physiological and pathological states of the cardiovascular and pulmonary systems, and finally touch on the current development of pharmacological inhibitors of PFKFB3 as potential therapeutics.
心血管疾病是世界范围内导致死亡的主要原因。代谢重编程和炎症是这类疾病的两个共同特征。双功能酶PFKFB(6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶)1至4因其在葡萄糖代谢中的关键功能而闻名。新出现的证据表明,PFKFB酶,特别是PFKFB3,是必不可少的免疫代谢调节因子,与心肺血管和其他病理有关。本文首先总结了PFKFB家族酶催化功能的结构基础,介绍了PFKFB3表达和活性调控及其非代谢功能的最新进展,然后阐述了PFKFB3的失调如何影响心血管和肺系统的生理和病理状态,最后介绍了PFKFB3药物抑制剂作为潜在治疗药物的最新进展。
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引用次数: 0
CPT1a Expression Is a Critical Cardioprotective Response to Pathological Stress That Enables Rescue by Gene Transfer. CPT1a表达的增加是对病理性应激的关键心脏保护反应,抑制重塑基因程序并通过基因转移实现拯救。
IF 16.2 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-16 Epub Date: 2025-12-04 DOI: 10.1161/CIRCRESAHA.125.327403
Andrew N Carley, Santosh K Maurya, Chandan K Maurya, Yang Wang, Amy Webb, Azariyas A Challa, Tatiana Gromova, Thomas M Vondriska, Zhentao Zhang, Hua Zhu, Ahlke Heydemann, Kenneth C Bedi, Christos P Kyriakopoulos, Craig H Selzman, Stavros G Drakos, Kenneth B Margulies, E Douglas Lewandowski

Background: CPT1 (carnitine palmitoyltransferase 1) is a rate-limiting enzyme for long-chain fatty acid oxidation. In adult hearts, CPT1b predominates, while CPT1a is coexpressed at lower levels. Pathological stress on the heart induces CPT1a expression, coinciding with a reduction in fatty acid oxidation, yet the role of CPT1a in pathological remodeling is unknown.

Methods: CPT1 isoform expression was assayed in the myocardium of patients with heart failure with nonischemic cardiomyopathy and a preclinical mouse model of heart failure. Mice were subjected to afterload stress via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, adeno-associated virus serotype 9 (AAV9)-mediated CPT1a overexpression (AAV9.cTnT [cardiac troponin T].Cpt1a) versus empty virus or PBS infusions as controls. MicroRNA 370, known to suppress hepatic CPT1a, was assayed and overexpressed to determine if microRNA 370 regulates cardiac CPT1a expression.

Results: CPT1a protein was elevated and microRNA 370 reduced in the myocardium of male and female patients with nonischemic cardiomyopathy, as well as in failing mouse hearts. AAV9-mediated microRNA 370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac-specific CPT1a knockout mice exacerbated adverse remodeling, severe dysfunction, and increased mortality. In contrast, CPT1a overexpression (2.8-fold) attenuated impaired ejection fraction (by 54%) versus control TAC hearts (P<0.05). Delivery of AAV9.cTnT.Cpt1a 4 weeks after TAC surgery led to significant rescue of ejection fraction and mitigated the exacerbated dysfunction of cardiac-specific CPT1a knockout mice TAC hearts. RNA-seq revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic, and cell death gene programs in both sham and TAC hearts, irrespective of changes in fatty acid oxidation, with reduced histone acetylation.

Conclusions: The effects of CPT1a in the heart extend beyond fatty acid oxidation including noncanonical regulation of gene programs. CPT1a upregulation occurs in nonischemic cardiomyopathy and is a critical cardioprotective adaptation to pathological stress.

背景:CPT1(肉碱棕榈酰转移酶1)是长链脂肪酸氧化的限速酶。在成人心脏中,CPT1b占主导地位,而CPT1a在较低水平上共表达。心脏的病理性应激诱导CPT1a表达,与脂肪酸氧化减少相一致,但CPT1a在病理性重塑中的作用尚不清楚。方法:检测CPT1亚型在心力衰竭合并非缺血性心肌病患者和临床前心力衰竭小鼠心肌中的表达。通过主动脉横缩术(TAC)或假手术(sham),小鼠受到心脏特异性CPT1a敲低或心脏特异性、腺相关病毒血清型9介导的CPT1a过表达(腺相关病毒血清型9)的负荷后应激。心肌肌钙蛋白T。Cpt1a)对照空病毒或PBS输注作为对照。已知抑制肝脏CPT1a的MicroRNA 370被检测并过表达,以确定MicroRNA 370是否调节心脏CPT1a的表达。结果:在男性和女性非缺血性心肌病患者以及衰竭小鼠心肌中,CPT1a蛋白升高,microRNA 370减少。腺相关病毒介导的microRNA 370在小鼠心脏中的过表达抑制了CPT1a的表达,并减弱了CPT1a对TAC的反应。在心脏特异性CPT1a敲除小鼠中,防止CPT1a对TAC的上调会加剧不良重构、严重功能障碍和死亡率增加。相比之下,与对照组相比,CPT1a过表达(2.8倍)减少了54%的射血分数(p结论:CPT1a在心脏中的作用超出了脂肪酸氧化,包括基因程序的非规范调节。CPT1a上调发生在非缺血性心肌病中,是对病理性应激的关键心脏保护适应。
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引用次数: 0
Meet the First Authors. 认识第一作者。
IF 16.2 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-16 Epub Date: 2026-01-15 DOI: 10.1161/RES.0000000000000744
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引用次数: 0
Fatty Acid Transport at the Heart of Metabolic Adaptation. 脂肪酸转运在代谢适应中的核心作用。
IF 20.1 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-15 DOI: 10.1161/circresaha.125.327929
Anja Karlstaedt
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引用次数: 0
Grhl3 Downregulation Facilitates ECM Adaptation for Fibroblast to iCM Commitment. Grhl3下调促进成纤维细胞向iCM承诺的ECM适应
IF 20.1 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-15 DOI: 10.1161/circresaha.125.327726
Xin Wu,Lanbing Liu,Yuanru Huang,Yi Ling,Fang Luo,Dongyu Gu,Mengxin Liu,Zhenhua Jia,Zhangyi Yu,Xiangjie Kong,Hong Ma,Yanggan Wang,Li Wang
BACKGROUNDDirect cardiac reprogramming offers a promising therapeutic strategy for heart regeneration by converting endogenous fibroblasts to functional induced cardiomyocytes (iCMs) that integrate into the myocardium to restore heart structure and function. While ECM (extracellular matrix) plays critical roles in cardiac disease and repair, the dynamic changes and transcriptional regulation underlying ECM remodeling during reprogramming remain poorly understood.METHODSWe investigated ECM dynamics during iCM reprogramming using integrated transcriptomic, proteomic, and epigenetic analyses, focusing on cell type-specific ECM components. A loss-of-function screen was used to identify critical ECM components and regulators, including Itga8 (integrin alpha-8) and Grhl3 (grainyhead-like protein 3 homolog), respectively, as reprogramming barriers. Mechanistic studies integrated RNA sequencing, mass spectrometry, and Cleavage Under Targets and Tagmentation to define Grhl3-dependent regulation. Functional outcomes were evaluated in vitro using decellularized ECM and in vivo using a myocardial infarction model with genetic lineage tracing.RESULTSCardiac reprogramming induced dynamic ECM remodeling, with significant changes in collagen, fibrillar proteins, and integrins. Itga8 was identified as a pivotal ECM component that restricts iCM conversion via the TGF-β (transforming growth factor-β)/SMAD pathway. Grhl3 emerged as a key transcriptional regulator for ECM components, including Itga8. ECM derived from Grhl3-deficient fibroblasts enhanced iCM induction, while Grhl3 depletion also reduced fibroblast activation and increased cellular plasticity. These effects synergized with TF (transcription factor)-mediated reprogramming to improve iCM efficiency, structural organization, and functional maturation. In vivo, removing Grhl3 enhanced fibroblast-to-cardiomyocyte conversion, reduced scar formation, and improved cardiac function after myocardial infarction.CONCLUSIONSOur findings establish ECM adaptation as a critical determinant of cardiac reprogramming and identify Grhl3 as a promising therapeutic target to advance myocardial repair strategies.
背景:直接心脏重编程为心脏再生提供了一种很有前景的治疗策略,通过将内源性成纤维细胞转化为功能诱导心肌细胞(iCMs),并整合到心肌中以恢复心脏结构和功能。虽然ECM(细胞外基质)在心脏疾病和修复中起着关键作用,但在重编程过程中ECM重塑的动态变化和转录调控仍然知之甚少。方法我们使用整合转录组学、蛋白质组学和表观遗传学分析来研究iCM重编程过程中的ECM动力学,重点研究细胞类型特异性ECM成分。功能丧失筛选用于鉴定关键的ECM成分和调节因子,包括Itga8(整合素α -8)和Grhl3(颗粒状头样蛋白3同源物),分别作为重编程障碍。机制研究整合了RNA测序、质谱分析、靶下切割和标记来定义grhl3依赖性调控。在体外使用去细胞化ECM评估功能结果,在体内使用具有遗传谱系追踪的心肌梗死模型评估功能结果。结果心肌重编程诱导动态ECM重构,胶原蛋白、纤维蛋白和整合素发生显著变化。Itga8被鉴定为通过TGF-β(转化生长因子-β)/SMAD途径限制iCM转化的关键ECM成分。Grhl3是ECM成分(包括Itga8)的关键转录调控因子。来自Grhl3缺失的成纤维细胞的ECM增强了iCM的诱导,而Grhl3缺失也降低了成纤维细胞的激活并增加了细胞的可塑性。这些效应与TF(转录因子)介导的重编程协同作用,提高iCM的效率、结构组织和功能成熟。在体内,去除Grhl3增强了成纤维细胞到心肌细胞的转化,减少了疤痕的形成,改善了心肌梗死后的心功能。结论我们的研究结果表明,ECM适应性是心脏重编程的关键决定因素,并确定Grhl3是推进心肌修复策略的有希望的治疗靶点。
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引用次数: 0
A Road Map to Understanding Cardiovascular Disease in Diabetes: From the AHA Strategically Focused Research Network in Cardiometabolic Health and Type 2 Diabetes. 了解糖尿病心血管疾病的路线图:来自美国心脏协会心脏代谢健康和2型糖尿病战略重点研究网络
IF 20.1 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-15 DOI: 10.1161/circresaha.125.325798
E Dale Abel,Rexford S Ahima,Ethan J Anderson,David D Berg,Jeffrey S Berger,Saumya Das,Mark W Feinberg,Edward A Fisher,Michael S Garshick,Chiara Giannarelli,Ira J Goldberg,Naomi M Hamburg,Sangwon F Kim,Filipe A Moura,Chiadi E Ndumele,Jonathan D Newman,Marc S Sabatine,Elizabeth Selvin,Ravi Shah
Despite major advances in medical therapies and prevention strategies, the risk of cardiovascular complications in patients with both type I and type II diabetes remains substantially elevated. In 2019, the American Heart Association sought applications for a Strategically Focused Research Network on Cardiometabolic Health and Type 2 Diabetes. In 2020, 4 centers were named, including Brigham and Women's Hospital, Johns Hopkins University, New York University, and the University of Iowa. These centers performed basic, translational, and clinical studies to provide insights to explain the over 2-fold risk of cardiovascular complications in diabetes. Clinical studies and studies in cells and animals aimed to uncover new mechanisms responsible for disease development. Studies using human populations sought to uncover new biomarkers to prognosticate risk. In this review, we discuss several key issues and current and developing methods to understand why diabetes drives atherosclerotic cardiovascular disease and heart failure. Both human data and experimental models are considered. We integrate a review of these topics with work from the Strategically Focused Research Network and conclude with suggestions for identifying novel risk factors and future experimental research.
尽管在医学治疗和预防策略方面取得了重大进展,但I型和II型糖尿病患者心血管并发症的风险仍然很高。2019年,美国心脏协会为心脏代谢健康和2型糖尿病战略重点研究网络寻求申请。2020年,有4个中心被命名,包括布里格姆妇女医院、约翰霍普金斯大学、纽约大学和爱荷华大学。这些中心进行了基础、转化和临床研究,以解释糖尿病患者心血管并发症超过2倍的风险。临床研究以及对细胞和动物的研究旨在揭示疾病发展的新机制。利用人类群体进行的研究试图发现新的生物标志物来预测风险。在这篇综述中,我们讨论了几个关键问题和当前和发展的方法来理解为什么糖尿病驱动动脉粥样硬化性心血管疾病和心力衰竭。同时考虑了人类数据和实验模型。我们将这些主题的回顾与战略重点研究网络的工作结合起来,最后提出了确定新的风险因素和未来实验研究的建议。
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引用次数: 0
Circulating CD34+ Fibroblast Progenitors Engaged in Heart Fibrosis of Allograft. 循环CD34+成纤维细胞祖细胞参与同种异体移植心脏纤维化。
IF 20.1 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2026-01-14 DOI: 10.1161/circresaha.125.326558
Xiaotong Sun,Ting Wang,Hui Gong,Yichao Qiu,Yuesheng Zhang,Mengjia Chen,Jianing Xue,Guoguo Ye,Rong Mou,Peng Teng,Weidong Li,Ting Chen,Li Zhang,Xiaogang Guo,Wei Mao,Haige Zhao,Liang Ma,Qingbo Xu
BACKGROUNDFibrosis is one of the major causes of cardiac allograft malfunction and is mainly driven by fibroblasts. However, the role of recipient-derived cells in generating allograft fibroblasts and the underlying mechanisms remain to be explored.METHODSWe analyzed human heart allograft samples and used murine transplant models (C57BL/6J, Cd34-CreERT2; R26-tdTomato, mRFP mice, Rosa26-iDTR, Postn-CreERT2; R26-tdTomato, double-tdTomato, and immunodeficient mice with BALB/c donors). Human progenitor cells were cultivated from blood. Single-cell RNA sequencing, Western blotting, quantitative polymerase chain reaction, and immunohistochemistry, whole-mount staining with 3-dimensional reconstruction, and in vivo/in vitro experiments were applied to characterize allograft cellular composition and communication.RESULTSSingle-cell RNA sequencing was introduced to delineate the allograft cell atlas of patients and mice. Y chromosome analysis identified that recipient-derived cells contributed to allograft fibroblasts in both patients and murine models. Combining the genetic cell lineage tracing technique, we found that recipient-derived CD34+ cells could give rise to activated fibroblasts. Bone marrow transplantation and parabiosis models revealed that the recipient's circulating non-bone marrow Cd34+ cells could generate allograft fibroblasts. Human CD34+ cells could differentiate into fibroblasts both in vivo and in vitro. CD34+ fibroblast progenitors were recruited by CXCL12-ACKR3 and MIF-ACKR3 interactions and differentiated via the TGFβ (transforming growth factor beta)/GFPT2 (glutamine-fructose-6-phosphate transaminase 2)/SMAD2/4 axis. Ablation of recipient Cd34+ cells reduced activated fibroblasts and alleviated allograft fibrosis.CONCLUSIONSWe identify circulating CD34+ cells as a novel source of fibroblast progenitors that contribute to cardiac allograft fibrosis, suggesting that targeting recipient CD34+ cells could be a novel therapeutic potential for treating cardiac fibrosis after heart transplantation.
背景:纤维化是同种异体心脏移植功能障碍的主要原因之一,主要由成纤维细胞驱动。然而,受体来源的细胞在产生同种异体移植成纤维细胞中的作用及其潜在机制仍有待探索。方法采用小鼠移植模型(C57BL/6J、Cd34-CreERT2、R26-tdTomato、mRFP小鼠、Rosa26-iDTR、Postn-CreERT2、R26-tdTomato、双tdtomato和BALB/c供体免疫缺陷小鼠)分析同种异体心脏移植样本。人类祖细胞是从血液中培养出来的。采用单细胞RNA测序、Western blotting、定量聚合酶链反应、免疫组织化学、三维重建全贴装染色和体内/体外实验来表征同种异体移植物的细胞组成和通讯。结果采用单细胞RNA测序技术绘制了患者和小鼠的同种异体移植细胞图谱。Y染色体分析发现,在患者和小鼠模型中,受体来源的细胞对同种异体移植成纤维细胞都有贡献。结合遗传细胞谱系追踪技术,我们发现受体来源的CD34+细胞可以产生活化的成纤维细胞。骨髓移植和异种共生模型显示,受体循环的非骨髓Cd34+细胞可以生成同种异体移植成纤维细胞。人CD34+细胞在体内和体外均可向成纤维细胞分化。CD34+成纤维细胞祖细胞通过CXCL12-ACKR3和MIF-ACKR3相互作用募集,并通过TGFβ(转化生长因子β)/GFPT2(谷氨酰胺-果糖-6-磷酸转氨酶2)/SMAD2/4轴分化。消融受体Cd34+细胞可减少活化的成纤维细胞,减轻同种异体移植物纤维化。结论:我们发现循环CD34+细胞是导致同种异体心脏移植纤维化的成纤维细胞祖细胞的新来源,这表明靶向受体CD34+细胞可能是治疗心脏移植后心脏纤维化的一种新的治疗潜力。
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引用次数: 0
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Circulation research
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