Defining Transcriptomic Heterogeneity between Left and Right Ventricle-Derived Cardiac Fibroblasts

Area of Science:

• Cardiovascular Biology
• Fibrosis Research
• Transcriptomics

Background:

• Cardiac fibrosis impairs heart function and is a hallmark of heart failure.
• Left ventricle (LV) and right ventricle (RV) fibrosis have distinct pathophysiologies.
• Cardiac fibroblasts (CFs) exhibit transcriptomic heterogeneity, but LV and RV CFs haven't been directly compared.

Purpose of the Study:

• To investigate baseline transcriptomic differences between LV and RV cardiac fibroblasts.
• To determine how these differences affect fibroblast behavior following pressure overload injury.
• To identify distinct fibroblast subpopulations in each ventricle and their roles in fibrosis.

Main Methods:

• Bulk RNA sequencing of CFs from healthy murine LV and RV.
• Single-cell RNA sequencing of LV and RV CFs.
• Analysis of CF subpopulations before and after pressure overload injury.

Main Results:

• LV-derived CFs showed a transcriptomic profile suggesting a more advanced myofibroblast transdifferentiation state compared to RV CFs.
• Baseline differences included enrichment of Postn+ CFs in the LV and Igfbp3+ CFs in the RV.
• Following injury, the LV developed more pro-fibrotic Thbs4+/Cthrc1+ CFs, while the RV showed expansion of Igfbp3+ and Inmt+ CF subpopulations.

Conclusions:

• LV and RV cardiac fibroblasts possess distinct baseline transcriptomic profiles.
• These intrinsic differences lead to divergent cellular responses to pressure overload injury.
• Understanding these subpopulations is crucial for developing targeted therapies for LV and RV fibrosis.