Zhejiang University Team Decodes Cardiac Fibrosis Mechanism: CD248 Identified as Key Therapeutic Target

Research Findings

The team employed single-cell RNA sequencing and spatial transcriptomics to analyze mouse and human heart tissues at various post-myocardial infarction stages. They identified a distinct fibroblast subpopulation with elevated CD248 expression, strongly associated with extracellular matrix remodeling. Genetic knockout and pharmacological interventions further elucidated CD248's role in cardiac fibrosis.

Figure 2. UMAP of fibroblast subpopulations in sham and myocardial infarction mouse hearts

In the chronic phase post-myocardial infarction, CD248+ fibroblasts expanded significantly, correlating with cardiac fibrosis and dysfunction. These cells upregulated ACKR3 expression by stabilizing TGFβRI, enhancing T-cell retention and activation.

In CD248 knockout (KO) mouse models, cardiac fibrosis and dysfunction were markedly reduced. Compared to wild-type mice, CD248 KO mice showed preserved cardiac function, reduced fibrotic area, and lower inflammatory cytokine levels after ischemia/reperfusion (I/R) injury.

Figure 3. CD248 deletion alleviates cardiac fibrosis and dysfunction in I/R and MI mouse models

Therapeutic Innovations

The team developed a CD248-targeted monoclonal antibody, IgG78, which significantly improved cardiac function post-I/R injury, reducing T-cell infiltration and inflammatory cytokines. Additionally, they engineered CD248-targeted chimeric antigen receptor (CAR) T-cells, which specifically eliminated CD248+ fibroblasts. This therapy reduced fibrosis, improved cardiac function, and suppressed T-cell infiltration, demonstrating dual benefits.

Figure 4. Schematic of IgG78 and CD248 CAR T-cell therapy in I/R mouse models

This study introduces novel therapeutic strategies for cardiac fibrosis, with potential for clinical trials through optimized CAR-T cell designs. The role of CD248 in other organs warrants further exploration.

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