Spatial multi-omic map of human myocardial infarction

Abstract

Myocardial infarction is a leading cause of death worldwide 1 . Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality 2 . Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.

Targeting the Immune-Fibrosis Axis in Myocardial Infarction and Heart Failure

“…Spatial transcriptomics data from human heart indicated that fibroblast populations were located within defined perivascular and interstitial spatial niches ( Supplementary Fig. 4B – E ) 25 .…”

“…The advent of single cell multi-omic technologies has afforded the opportunity for the high-resolution detection of novel cell states from healthy and diseased human tissue including the heart 19, 20, 22, 23, 25, 28 . These human cell atlases have provided new insights into the cellular landscape of HF and identified unexpected cell diversity within the stromal compartment.…”

Identification of Adipose Tissue as a Reservoir of Macrophages after Acute Myocardial Infarction

“…Furthermore, spatial multi-omic mapping of human myocardial infarction also reveals that a given cell state changes based on the cells’ neighborhood. For example, gene-regulatory programs driving injury of cardiomyocytes, activated phagocytic macrophages and their relation to myofibroblast differentiation in cardiac tissue remodeling are dependent on specific myocardial tissue zones and disease stages [ 26 ]. Hence, tissue macrophage heterogeneity is a critical determinant of immune responses and likely governs the distinct ability of human or mouse macrophages to shape the infarcted heart.…”

Cardiac remodelling – Part 1: From cells and tissues to circulating biomarkers. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology

“…The clinical significance of these specific subpopulations of fibroblasts will need further investigation considering the preeminent role of cardiac fibrosis in cardiac remodelling of different aetiologies. In another study, spatial transcriptomics identified two temporal stages in myocardial scar formation: an early scar with high hypoxia signalling and low ECM production, and a more mature scar with increased ECM production 168 . Genes including TGFB3 and PDGFRA are abundantly expressed in the mature scar, while SERPINE1 is more expressed in the early scar.…”