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Updated: Dec 8, 2025
Refined CLARITY-Based Tissue Clearing for Three-Dimensional Fibroblast Organization in Healthy and Injured Mouse Hearts
Published on: May 16, 2021
Human cardiac fibroblasts expressing VCAM1 improve heart function in postinfarct heart failure rat models by
Takahiro Iwamiya1,2, Bertrand-David Segard1, Yuimi Matsuoka1
1Research & Development Department, Metcela Inc., Kawasaki, Kanagawa, Japan.
Insights
Specific cardiac fibroblasts (CFs) expressing vascular cell adhesion molecule 1 (VCAM1) can repair heart damage. These VCAM1-expressing CFs (VCFs) promote lymphatic vessel formation and restore cardiac function after injury.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Cardiac Fibroblast Research
Background:
- Cardiovascular diseases cause significant mortality globally.
- Myocardial ischemic injury leads to cell death and impaired heart function.
- Cardiac fibroblasts (CFs) are crucial for cardiac repair, but their heterogeneity and mechanisms remain unclear.
Purpose of the Study:
- To investigate if a specific CF subpopulation can repair injured myocardium and restore cardiac function.
- To explore the role of vascular cell adhesion molecule 1 (VCAM1) expression in CFs.
- To understand the molecular mechanisms underlying CF-mediated cardiac repair.
Main Methods:
- Flow cytometry to identify CF subpopulations based on VCAM1 expression.
- Whole-transcriptome analysis to compare gene expression profiles.
- In vitro vascular formation assays.
- In vivo studies using a rat model of postinfarct heart failure.
Main Results:
- Two CF subpopulations were identified: VCAM1-expressing (VCFs) and non-expressing.
- VCFs showed distinct gene expression profiles, correlating with lymphangiogenesis-related genes.
- VCFs significantly enhanced lymphatic cell network complexity in vitro.
- VCF injection in rats improved left ventricular ejection fraction and fractional shortening.
- Histology confirmed VCFs mobilized lymphatic endothelial cells into the infarcted area.
Conclusions:
- Human CFs are heterogeneous, with VCAM1 expression linked to lymphangiogenesis factors.
- VCFs restore cardiac mechanical properties by promoting lymphatic vessel formation in infarct zones.
- This CF subpopulation plays a role in cardiac regeneration and lymphatic system homeostasis.
Abstract:
Cardiovascular diseases are a leading cause of death worldwide. After an ischemic injury, the myocardium undergoes severe necrosis and apoptosis, leading to a dramatic degradation of function. Numerous studies have reported that cardiac fibroblasts (CFs) play a critical role in heart function even after injury. However, CFs present heterogeneous characteristics according to their development stage (i.e., fetal or adult), and the molecular mechanisms by which they maintain heart function are not fully understood. The aim of this study is to explore the hypothesis that a specific population of CFs can repair the injured myocardium in heart failure following ischemic infarction, and lead to a significant recovery of cardiac function. Flow cytometry analysis of CFs defined two subpopulations according to their relative expression of vascular cell adhesion molecule 1 (VCAM1). Whole-transcriptome analysis described distinct profiles for these groups, with a correlation between VCAM1 expression and lymphangiogenesis-related genes up-regulation. Vascular formation assays showed a significant stimulation of lymphatic cells network complexity by VCFs. Injection of human VCAM1-expressing CFs (VCFs) in postinfarct heart failure rat models (ligation of the left anterior descending artery) led to a significant restoration of the left ventricle contraction. Over the course of the experiment, left ventricular ejection fraction and fractional shortening increased by 16.65% ± 5.64% and 10.43% ± 6.02%, respectively, in VCF-treated rats. Histological examinations revealed that VCFs efficiently mobilized the lymphatic endothelial cells into the infarcted area. In conclusion, human CFs present heterogeneous expression of VCAM1 and lymphangiogenesis-promoting factors. VCFs restore the mechanical properties of ventricular walls by mobilizing lymphatic endothelial cells into the infarct when injected into a rat heart failure model. These results suggest a role of this specific population of CFs in the homeostasis of the lymphatic system in cardiac regeneration, providing new information for the study and therapy of cardiac diseases.
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