Human cardiac fibroblasts expressing VCAM1 improve heart function in postinfarct heart failure rat models by stimulating lymphangiogenesis

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.

Local Injection of Hydroxyapatite Electret Ameliorated Infarct Size After Myocardial Infarction

“… 20 Iwamiya et al reported that local injection of human VCAM1-expressing cardiac fibroblasts in a postinfarct rat model led to a significant restoration of LV contraction by mobilizing lymphatic endothelial cells into the infarct area. 21 These angiogenic and lymphangiogenic effects may also contribute to the beneficial effects of HAE seen in the present study. However, the possibility remains that the increases in Icam1 and Vcam1 may simply reflect increases in endothelial cells through the HIF1α-CXCL12/VEGF signaling pathway.…”

Lymphatic Clearance of Immune Cells in Cardiovascular Disease

“…This population expresses several pro-lymphangiogenic factors, including VEGF-C, and was shown to promote lymphangiogenesis as assessed by assays for in vitro tube formation. Furthermore, injection of human foetal CFV in post-infarct heart failure rat models mobilised LECs into the infarcted area and restored cardiac contractility [158].…”

The role of lymphangiogenesis in cardiovascular diseases and heart transplantation

“…Overexpressed AM induces cardiac lymphangiogenesis after MI, resulting in improved cardiac function and reduced myocardial edema via regulation of connexin 43 [71]. In post-infarct heart failure rat models, cardiac fibroblasts expressing vascular cell adhesion molecule-1 (VCAM-1) improve heart function by triggering lymphangiogenesis [14]. A combined delivery of lymphatic endothelial progenitor cells (LEPCs) and VEGF-C with the functionalized self-assembling peptide (SAP), or delivery of SAP-thymosin β4 (Tβ4) has shown to be effective for enhancing cardiac lymphangiogenesis after MI, reducing cardiac inflammation and edema, attenuating reverse myocardial remodeling, and improving cardiac function and repair of the infarcted myocardium [132,133].…”

“…The important findings suggest that the use of REELIN could be a valuable therapeutic approach to improve cardiac function in humans [12]. Moreover, a growing body of evidence indicates that lymphangiogenesis is an active participant in the pathogenesis of atherosclerosis and myocardial infarction (MI) [13][14][15]. Vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR-3 facilitate lymphangiogenesis and lymphatic function, which may provide a pathway for inflammatory cell efflux, favoring the resolution of cardiac edema and wound healing within the injured heart [16].…”