Dynamic molecular atlas of cardiac fibrosis at single-cell resolution shows CD248 in cardiac fibroblasts orchestrates interactions with immune cells.

Summary

Using single-cell and spatial transcriptomics across human and mouse infarcted hearts, the authors identify a CD248hi fibroblast subset that coordinates immune-fibroblast crosstalk. Fibroblast-specific Cd248 deletion reduces fibrosis and dysfunction; mechanistically, CD248 stabilizes TGFβRI and induces ACKR3, retaining T cells that fuel fibroblast activation. Disrupting this axis with an antibody or engineered T cells lowers T-cell infiltration and scar expansion.

Key Findings

• Identified a CD248hi fibroblast subset tightly linked to extracellular matrix remodeling using single-cell and spatial transcriptomics.
• Fibroblast-specific Cd248 deletion reduced cardiac fibrosis and dysfunction after ischemia/reperfusion.
• CD248 stabilizes TGFβRI and upregulates ACKR3 in fibroblasts, enhancing T-cell retention; disrupting this via antibody or engineered T cells reduced T-cell infiltration and scar expansion.

Clinical Implications

Suggests CD248 as a therapeutic target for post-infarction remodeling; antibody- or cell-based strategies disrupting fibroblast–T cell retention loops may attenuate fibrosis and preserve function.

Limitations

• Predominantly preclinical with limited human functional validation beyond transcriptomic association
• Safety and specificity of CD248 targeting in the heart and other organs remain to be established

Future Directions

Advance CD248-directed therapeutics (antibodies, cellular therapies) into large-animal models and early clinical studies; biomarker development to identify CD248hi fibroblast activity in patients.