Stable and functional regulatory T cell attenuates fibrotic remodeling in heart failure

IF 4 3区环境科学与生态学 Q3 CELL & TISSUE ENGINEERING

Regenerative Therapy Pub Date : 2026-03-01 Epub Date: 2026-02-28 DOI:10.1016/j.reth.2026.101079

Takura Taguchi , Takuji Kawamura , Norihisa Mikami , Kosuke Torigata , Akima Harada , Lisa Fujimura , Emiko Ito , Maki Takeda , Kenji Miki , Shimon Sakaguchi , Shigeru Miyagawa

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引用次数: 0

Abstract

Introduction

Heart failure involves myocardial fibrosis and impaired cardiac function. The transverse aortic constriction (TAC) model in mice replicates pressure overload-induced fibrosis. Immune-mediated inflammation, particularly through T lymphocytes and macrophages, plays a pivotal role in the progression of fibrosis. In vitro–induced regulatory T cells (Tregs) are limited by Foxp3 instability. To address this, stable and functional in vitro induced Tregs (S/F-iTregs) have been developed under CD28-deprived conditions, exhibiting sustained Foxp3 expression and epigenetic stability. We aimed to evaluate the therapeutic efficacy of intravenously administered S/F-iTregs in a murine TAC model of heart failure.

Methods

S/F-iTregs were generated from CD4⁺ conventional T cells under CD28 costimulation-deficient conditions. BALB/c mice underwent TAC surgery and received S/F-iTregs intravenously. Cardiac function was assessed by echocardiography. Myocardial fibrosis was evaluated using histological staining. Bulk RNA sequencing was performed to assess transcriptomic changes in the myocardium.

Results

S/F-iTreg administration significantly improved left ventricular function and reduced myocardial fibrosis compared to those in controls. PKH26-labeled S/F-iTregs were detected within the cardiac tissue, confirming in vivo migration. RNA sequencing revealed downregulation of inflammation- and fibrosis-related pathways, including tumor necrosis factor-alpha/nuclear factor kappa-light-chain-enhancer of activated B cell, platelet-derived growth factor, transforming growth factor-beta signaling, and modulation of macrophage-related transcriptional programs.

Conclusions

Systemic administration of S/F-iTregs attenuates cardiac fibrosis and preserves cardiac function in pressure overload–induced heart failure. These findings support S/F-iTreg–based immunomodulation as a potential approach to limit adverse fibrotic cardiac remodeling.

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稳定和功能性调节性T细胞减弱心力衰竭的纤维化重塑。

心衰包括心肌纤维化和心功能受损。小鼠主动脉横缩（TAC）模型可复制压力过载诱导的纤维化。免疫介导的炎症，特别是通过T淋巴细胞和巨噬细胞，在纤维化的进展中起着关键作用。体外诱导的调节性T细胞（Tregs）受到Foxp3不稳定性的限制。为了解决这个问题，在cd28缺失的条件下，研究人员开发了稳定和功能性的体外诱导Tregs (S/F-iTregs)，显示出持续的Foxp3表达和表观遗传稳定性。我们的目的是评估静脉给药S/F-iTregs对心力衰竭小鼠TAC模型的治疗效果。方法：CD4+常规T细胞在CD28共刺激缺乏条件下生成S/F-iTregs。BALB/c小鼠接受TAC手术并静脉注射S/F-iTregs。超声心动图评估心功能。采用组织学染色评价心肌纤维化。进行大量RNA测序以评估心肌的转录组变化。结果：与对照组相比，S/F-iTreg显著改善左心室功能，减少心肌纤维化。在心脏组织中检测到pkh26标记的S/F-iTregs，证实其在体内迁移。RNA测序显示炎症和纤维化相关通路下调，包括活化B细胞的肿瘤坏死因子- α /核因子- kappa-轻链增强子、血小板来源的生长因子、转化生长因子- β信号传导和巨噬细胞相关转录程序的调节。结论：全身给药S/F-iTregs可减轻压力负荷引起的心力衰竭患者的心脏纤维化并维持心功能。这些发现支持基于S/ f - itregg的免疫调节作为限制不良纤维化心脏重构的潜在方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Regenerative Therapy Engineering-Biomedical Engineering

CiteScore

6.00

自引率

2.30%

发文量

106

审稿时长

49 days

期刊介绍： Regenerative Therapy is the official peer-reviewed online journal of the Japanese Society for Regenerative Medicine. Regenerative Therapy is a multidisciplinary journal that publishes original articles and reviews of basic research, clinical translation, industrial development, and regulatory issues focusing on stem cell biology, tissue engineering, and regenerative medicine.