A Newly Curated Single Cell Sequencing Atlas Predicts Efferocytic-dependent Crosstalk in Hearts
5 affiliations
- 1Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- 2Institute for Artificial Intelligence in Medicine, Center for Deep Phenotyping and Precision Therapeutics, Northwestern University, Chicago, IL, USA
- 3Indiana University, Division of Cardiovascular Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- 4Lurie Children’s Hospital, Heart Center, Chicago, IL, USA
- 5Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Abstract
Cardiac repair after myocardial infarction (MI) requires coordinated immune cell communication, yet the signaling networks mediating this process and how they are disrupted in disease remain incompletely defined. MERTK, a receptor tyrosine kinase expressed on macrophages, promotes inflammation resolution, and its loss leads to inefficient cardiac repair. To investigate how MERTK shapes cardiac immune communication at single-cell resolution, we constructed a curated cardiac immune cell atlas integrating 36,932 cells/nuclei from 8 murine cardiac RNA sequencing datasets, yielding 22 annotated cell populations spanning myeloid, lymphoid, endothelial, and stromal compartments. We developed a cardiac-specific k-nearest neighbor classifier trained on this atlas that achieved an enhanced weighted F1 versus other widely used platforms. Applying our classifier to Mertk knockout (KO) versus control adult mice at 7 days post-MI revealed striking compositional differences including B cell expansion, reduction of CCR2+ macrophages, and enrichment of MHCII macrophages. The data are consistent with a shift from monocyte-derived macrophage-coordinated activation versus sustained adaptive immune activation. CellChat analysis revealed a reduction in total predicted interactions in KOs alongside near-doubling of per-interaction signaling strength. ARG1+ macrophages selectively lost SPP1 autocrine self-renewal signatures in KOs while preserving outgoing stromal signals. Moreover, a multi-sender Cyclophilin A-CD147 program deployed by mature macrophages across the stromal compartment was reprogrammed in KOs so that MHCII macrophages replaced mature macrophage subtypes as the predicted sender. These findings implicate MERTK in shaping macrophage identity and influencing the predicted intercellular communication architecture of the post-MI heart.
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BibTeX
@article{meite2026newly,
title = {{A Newly Curated Single Cell Sequencing Atlas Predicts Efferocytic-dependent Crosstalk in Hearts}},
author = {Isaac Meite and Lorenzo Pesce and Matthew Feinstein and Edward B. Thorp and Connor W. Lantz},
journal = {American journal of physiology. Heart and circulatory physiology},
year = {2026},
month = oct,
doi = {10.1152/ajpheart.00475.2026},
url = {https://doi.org/10.1152/ajpheart.00475.2026},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - A Newly Curated Single Cell Sequencing Atlas Predicts Efferocytic-dependent Crosstalk in Hearts
AU - Isaac Meite
AU - Lorenzo Pesce
AU - Matthew Feinstein
AU - Edward B. Thorp
AU - Connor W. Lantz
PY - 2026
DA - 2026/10/22
JO - American journal of physiology. Heart and circulatory physiology
DO - 10.1152/ajpheart.00475.2026
UR - https://doi.org/10.1152/ajpheart.00475.2026
AB - Cardiac repair after myocardial infarction (MI) requires coordinated immune cell communication, yet the signaling networks mediating this process and how they are disrupted in disease remain incompletely defined. MERTK, a receptor tyrosine kinase expressed on macrophages, promotes inflammation resolution, and its loss leads to inefficient cardiac repair. To investigate how MERTK shapes cardiac immune communication at single-cell resolution, we constructed a curated cardiac immune cell atlas integrating 36,932 cells/nuclei from 8 murine cardiac RNA sequencing datasets, yielding 22 annotated cell populations spanning myeloid, lymphoid, endothelial, and stromal compartments. We developed a cardiac-specific k-nearest neighbor classifier trained on this atlas that achieved an enhanced weighted F1 versus other widely used platforms. Applying our classifier to Mertk knockout (KO) versus control adult mice at 7 days post-MI revealed striking compositional differences including B cell expansion, reduction of CCR2+ macrophages, and enrichment of MHCII macrophages. The data are consistent with a shift from monocyte-derived macrophage-coordinated activation versus sustained adaptive immune activation. CellChat analysis revealed a reduction in total predicted interactions in KOs alongside near-doubling of per-interaction signaling strength. ARG1+ macrophages selectively lost SPP1 autocrine self-renewal signatures in KOs while preserving outgoing stromal signals. Moreover, a multi-sender Cyclophilin A-CD147 program deployed by mature macrophages across the stromal compartment was reprogrammed in KOs so that MHCII macrophages replaced mature macrophage subtypes as the predicted sender. These findings implicate MERTK in shaping macrophage identity and influencing the predicted intercellular communication architecture of the post-MI heart.
SN - 0363-6135
SN - 1522-1539
ER -