Midkine Prevents Calcification of Aortic Valve Interstitial Cells via Intercellular Crosstalk

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Genomics

Background:

• Calcified aortic valve disease (CAVD) is the most prevalent valvular heart disease, yet its underlying mechanisms and effective pharmaceutical treatments remain elusive.
• The complex cellular environment of CAVD exhibits significant heterogeneity, necessitating detailed analysis of cell diversity and communication to understand disease progression.

Purpose of the Study:

• To comprehensively map the transcriptomic landscape and intercellular communication networks within the aortic valve.
• To identify key cellular players and molecular pathways involved in the pathogenesis of CAVD.
• To explore potential therapeutic targets for mitigating CAVD progression.

Main Methods:

• Single-cell RNA sequencing (sc-RNA-seq) was employed to analyze the transcriptomic profiles of aortic valve cells.
• Cell-cell interaction analysis was performed to identify communication pathways.
• In vitro assays, including Alizarin Red S staining, RT-qPCR, and Western blotting, were used to validate findings on MDK's role in calcification.

Main Results:

• Single-cell RNA sequencing revealed significant cellular heterogeneity in the aortic valve.
• Transitional valvular endothelial cells (tVECs) were identified as a potential target for modulating endothelial-to-mesenchymal transition (EndMT).
• Matrix valvular interstitial cells (mVICs) expressing midkine (MDK) were found to interact with other interstitial cell types, with MDK inhibiting VIC calcification.

Conclusions:

• The study delineates the heterogeneity of aortic valve cells and highlights the critical role of intercellular communication.
• Midkine (MDK) secreted by mVICs demonstrates an inhibitory effect on valvular interstitial cell (VIC) calcification.
• MDK presents a potential therapeutic strategy for developing novel inhibitors against CAVD.