Spatial and Functional Immune Profiling Identifies Impaired Vascular Repair in Human Myocardial Infarction
Amankeldi A Salybekov1,2,3, Saida Shaikalamova4, Aiman Kinzhebay1
1Regenerative Medicine Division, Cell and Gene Therapy Department, Qazaq Institute of Innovative Medicine, Astana 010000, Kazakhstan.
Insights
In human myocardial infarction (MI), immune cells like CD8+ T cells infiltrate damaged heart tissue, driven by antigen-presenting cells (APCs). This process, alongside impaired vascular repair, contributes to heart healing complexities.
Area of Science:
- Cardiovascular Biology
- Immunology
- Regenerative Medicine
Background:
- Previous murine studies showed CD8 cells and myeloid dendritic cells (mDCs) infiltrate the infarcted myocardium post-myocardial infarction (MI).
- The spatial interaction between CD8+ T cells and dendritic cells in human MI remains poorly understood.
Purpose of the Study:
- To characterize immune-stromal dynamics in human infarcted myocardium and peripheral blood using spatial transcriptomics.
- To investigate the interplay between immune cells and stromal components in the context of human MI.
Main Methods:
- Spatial transcriptomics of human myocardium at 2 and 6 days post-MI.
- Peripheral blood flow cytometry and endothelial progenitor cell (EPC) colony-forming assays.
- Cell composition, pathway enrichment, and cell-to-cell communication analyses.
Main Results:
- Dynamic shifts in immune, fibroblast, and endothelial populations were observed in infarcted myocardium.
- CD8+ T cells accumulated in ischemic regions, while circulating levels decreased.
- Antigen-presenting cells (APCs) increased in infarct zones, promoting T cell recruitment via APC-endothelial crosstalk; EPC function was impaired in MI patients.
Conclusions:
- APC-driven CD8+ T cell recruitment and EPC dysfunction are critical in human MI.
- Immune-endothelial interactions facilitate early T cell infiltration, but impaired progenitor cells limit vascular repair.
- Findings offer mechanistic insights into immune-vascular imbalance during infarct healing and suggest therapeutic targets.
Abstract:
Background: In an earlier murine model of myocardial infarction (MI), we showed that CD8 cells and myeloid dendritic cells (mDCs) infiltrate the infarcted myocardium within the first week. However, in humans, the spatial interplay between CD8+ T cells and dendritic cells in the spatial context of human myocardial infarction remains underexplored. Objective: In the present study, we applied spatial transcriptomics and functional assays to characterize immune-stromal dynamics in infarcted myocardium and peripheral blood. Methods & Results: Spatial transcriptomics analysis of infarcted human myocardium at days 2 and 6 post-MI, combined with peripheral blood flow cytometry and EPC colony-forming assays, was performed. Cell composition, pathway enrichment, and cell-to-cell communication analyses were conducted to map immune-stromal cells' dynamics across time points. Spatial mapping identified dynamic shifts in immune, fibroblast, and endothelial populations, with fibroblasts and endothelial cells remaining abundant throughout. CD8+ T cells accumulated in ischemic regions while their circulating levels declined. Gene Ontology and pathway analyses of CD8A+ transcripts revealed enrichment of proinflammatory and NF-κB survival programs. ITGAX/CD33/THBD+ APCs progressively increased within infarct zones, activating antigen-presentation and leukocyte chemotaxis pathways. Early (day 2) APC-endothelial crosstalk showed the strongest predicted recruitment signals for CD8+ T cells, which diminished by day 6. Finally, EPC colony-forming capacity showed a tendency for reduction in MI patients and inversely correlated with coronary lesion burden, indicating impaired vascular repair potential. Conclusions: This integrative spatial and functional study demonstrates that APC-driven CD8+ recruitment and EPC dysfunction are key features of human MI. Immune-endothelial niches facilitate early cytotoxic T-cell infiltration, while progenitor depletion limits vascular regeneration. These findings provide mechanistic insight into immune-vascular imbalance during infarct healing and highlight potential therapeutic targets to modulate inflammation and restore vascular repair.
