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© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Myocardial infarction (MI) remains the leading cause of death worldwide. We previously found that a specific population of human fetal cardiac fibroblasts (fCFs), which express vascular cell adhesion molecule 1 (VCAM1), have cardioprotective effects after MI, inducing reparative cardiac lymphangiogenesis. This study investigated whether adult cardiac fibroblasts (aCFs), which are more feasible for autologous transplantation, differ in surface marker expression and lymphangiogenic potential compared to fCFs. Furthermore, we examined whether aCFs could be exogenously manipulated to acquire fCF-like lymphangiogenic potential and serve as a cell therapy for MI and MI-associated heart failure. In vivo MI models (rat and mouse) and in vitro coculture assays with lymphatic endothelial cells were conducted. We found that TNF-α and IL-4 stimulation induced aCFs to express VCAM1 via NF-κB and STAT6 signaling, yielding a subpopulation termed adult VCAM1+ cardiac fibroblasts (aVCFs). These aVCFs, distinct from myofibroblasts, expressed CD90 and improved cardiac function post-MI. Adrenomedullin (ADM) was identified as a key paracrine effector, and its knockdown attenuated the pro-lymphangiogenic and cardioprotective effects of aVCFs. Our findings demonstrate that aVCFs promote cardiac lymphangiogenesis and protect cardiac function following MI, highlighting their potential as an autologous cell therapy.

Details

Title
Adrenomedullin production by adult cardiac fibroblasts via NF-κB/STAT6 signaling enhances post-infarction lymphangiogenesis and cardiac repair
Author
Matsuoka, Yuimi 1 ; Shimizu, Yuuki 2 ; Luo, Haihang 2 ; Segard, Bertrand-David 3 ; Matsuyama, Makoto 4 ; Hayashi, Takumi 2 ; Murohara, Toyoaki 2 ; Iwamiya, Takahiro 5 

 Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, 466-8550, Nagoya, Japan (ROR: https://ror.org/04chrp450) (GRID: grid.27476.30) (ISNI: 0000 0001 0943 978X); Advanced Regenerative Cell-Based Healthcare Education for Resources, Nagoya University Graduate School of Medicine, Nagoya, Japan (ROR: https://ror.org/04chrp450) (GRID: grid.27476.30) (ISNI: 0000 0001 0943 978X); Research & Development Department, LYMPHOGENiX Ltd, Covent Garden, London, England (ROR: https://ror.org/05wnh3t63) (GRID: grid.421947.d) (ISNI: 0000 0004 1782 6335) 
 Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, 466-8550, Nagoya, Japan (ROR: https://ror.org/04chrp450) (GRID: grid.27476.30) (ISNI: 0000 0001 0943 978X) 
 Advanced Regenerative Cell-Based Healthcare Education for Resources, Nagoya University Graduate School of Medicine, Nagoya, Japan (ROR: https://ror.org/04chrp450) (GRID: grid.27476.30) (ISNI: 0000 0001 0943 978X) 
 Department of Otorhinolaryngology, Faculty of Medicine, Juntendo University, Tokyo, Japan (ROR: https://ror.org/01692sz90) (GRID: grid.258269.2) (ISNI: 0000 0004 1762 2738) 
 Advanced Regenerative Cell-Based Healthcare Education for Resources, Nagoya University Graduate School of Medicine, Nagoya, Japan (ROR: https://ror.org/04chrp450) (GRID: grid.27476.30) (ISNI: 0000 0001 0943 978X); Research & Development Department, LYMPHOGENiX Ltd, Covent Garden, London, England (ROR: https://ror.org/05wnh3t63) (GRID: grid.421947.d) (ISNI: 0000 0004 1782 6335); Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan (ROR: https://ror.org/02kn6nx58) (GRID: grid.26091.3c) (ISNI: 0000 0004 1936 9959) 
Pages
32098
Section
Article
Publication year
2025
Publication date
2025
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3251276874
Copyright
© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.