Abstract 12020: Heterogeneity and Plasticity of Cardiac Fibroblasts Governing Reparative Lymphangiogenesis After Myocardial Infarction: A New Therapeutic Approach for Heart Failure

Introduction: Cardiac lymphangiogenesis has attracted attention as a therapeutic target after myocardial infarction (MI). Lymphangiogenic remodeling has been observed after MI in adult and fetal hearts; however, reparative lymphangiogenic remodeling is only observed in fetal hearts. The factors that determine the fate of this phenomenon have not been fully elucidated. Hypothesis: We demonstrated that a specific population of VCAM1 + human fetal cardiac fibroblasts (fCFs) restore cardiac function post-MI by lymphangiogenesis. Thus, we hypothesize that adult cardiac fibroblasts (aCFs), compared to fCFs, possess a different distribution of fibroblasts with differing lymphangiogenic potential. Furthermore, we also hypothesize that aCFs can be exogenously manipulated to acquire fCFs-like reparative lymphangiogenic potential, which can be used as a cell therapy for heart failure. Methods: Flow cytometry assessed CD90 and VCAM1 expression of aCFs and fCFs. To shift aCFs towards a fCF phenotype, TNF-α and IL-4 were added to culture medium. aCF subpopulations were intramyocardially injected in nude rats and swine post-MI with subsequent echocardiography. Myocardial tissue staining (Sirius Red, LYVE1) and RNA-seq were performed to identify the molecular mechanism. Results: aCFs and fCFs exhibited different distributions of CD90 and VCAM1 expression, where aCFs showed lower CD90 and VCAM1 expression. The addition of TNF-α and IL-4 shifted the localization of VCAM1 + aCFs towards a fCF distribution by activation of NF-κB. VCAM1 + CD90 + fCFs-like aCFs provided a sustained improvement in left ventricular ejection fraction and showed reduced fibrosis and increased lymphangiogenesis. This effect was recapitulated in a large animal model. In terms of the molecular mechanism, 13 candidate genes were identified. Conclusions: These findings suggest that the heterogenous and plastic polarity of aCFs and fCFs determines the fate of the lymphangiogenic response after MI and that this response can be regulated by 13 genes. This artificial creation of the VCAM1 + fCFs-like fibroblast environment after MI has enabled a clinical trial for a new cell therapy for inducing reparative lymphangiogenesis (clinical trial ID: jRCT2033210078).