Leptin Receptor Fibroblasts Are Preferential Contributors to Cardiac Fibrosis

Area of Science:

• Cardiovascular Biology
• Fibrosis Research
• Cellular Heterogeneity

Background:

• Cardiac fibrosis is a key feature of heart failure.
• The role of cardiac fibroblast (CF) heterogeneity in fibrosis is not well understood.

Purpose of the Study:

• To investigate the contribution of specific cardiac fibroblast subpopulations to cardiac fibrosis.
• To identify the role of leptin signaling in cardiac remodeling.

Main Methods:

• Lineage tracing and depletion of specific CF subpopulations in murine myocardial infarction models.
• Transcriptional and epigenetic analysis of fibroblast subsets.
• Single-cell RNA sequencing and histological examination of human cardiac tissue.

Main Results:

• Fibroblasts expressing the leptin receptor (LepR+) were identified as a distinct CF subpopulation in the coronary adventitia.
• LepR+ CFs proliferated significantly after myocardial infarction and were a major source of scar tissue.
• Genetic ablation of LepR+ CFs attenuated cardiac fibrosis and improved cardiac function.
• LepR+ CFs were also found in the human heart, associated with adipocytes.

Conclusions:

• Adventitial LepR+ fibroblasts are critical drivers of pathological cardiac remodeling and fibrosis.
• Cardiac fibroblasts, not cardiomyocytes, are the primary responders to leptin in the heart.
• These findings redefine the role of leptin signaling in cardiac disease progression.