Spatiotemporal dissection and ultrasound-targeted modulation of the COL6A1–LAMININ signalling axis in post-myocardial infarction border zone fibrosis
L Qian, C Yang, X Zhang, D XuAbstract
Background
Maladaptive ventricular remodelling after myocardial infarction (MI) is driven by persistent expansion of fibrosis within the infarct border zone, a spatially heterogeneous niche exposed to chronic hypoxia, inflammation and biomechanical stress. The molecular mechanisms governing the transition from adaptive scar formation to pathological fibrosis remain incompletely defined.
Purpose
To identify the mechanistic role and spatiotemporal dynamics of the COL6A1–LAMININ signalling axis in border zone fibrotic remodelling and to evaluate whether spatially confined ultrasound-mediated intervention can reprogram profibrotic fibroblast fate.
Methods
Integrated single-cell RNA sequencing and spatial transcriptomics were applied to map cellular states and extracellular matrix (ECM) signalling architecture across defined spatial compartments and sequential time points after MI. Ligand–receptor interaction modelling, trajectory inference and pathway analysis were used to delineate regulatory networks driving fibroblast activation. A targeted ultrasound-triggered phase-transition nanocarrier system was employed to achieve temporally controlled and spatially restricted modulation of selected fibroblast subsets in vivo. Structural remodelling, molecular signatures and cardiac function were systematically evaluated.
Results
A distinct COL6A1 high fibroblast subset accumulated selectively in the border zone during late remodelling. Spatial mapping revealed coordinated enrichment of laminin-211 and integrin α1, forming a localised ECM signalling niche. Mechanistically, laminin-211–integrin α1 engagement activated focal adhesion kinase–Src signalling, reinforcing a self-sustaining profibrotic transcriptional programme. Trajectory analysis identified a critical temporal window during which reparative fibroblasts transitioned towards a pathological ECM-producing state. Ultrasound-guided modulation of the COL6A1–LAMININ axis disrupted this signalling loop, attenuated ECM deposition, reduced profibrotic gene expression and improved structural remodelling without detectable off-target injury.
Conclusion
These findings identify the COL6A1–LAMININ axis as a spatially organised mechanotransductive hub governing pathological fibroblast fate in the MI border zone. Spatiotemporally controlled ultrasound targeting enables precision reprogramming of fibrotic niches and represents a translational strategy for reversing maladaptive post-MI remodelling.