Spatial organization of fibroblast subpopulations and niches across acute repair and chronic fibrotic remodeling of the human myocardium
- 1Universitatsklinikum Dusseldorf
Abstract
Myocardial fibrosis is a common end point of acute and chronic cardiovascular injury, yet the spatially organized fibroblast (Fb) and immune-cell states that sustain fibrotic remodeling across etiologies remain incompletely defined. We applied cyclic in situ hybridization (cISH)-based spatial transcriptomics to myocardial biopsies from patients with acute myocardial infarction (AMI), ischemic cardiomyopathy (ICM), hypertrophic cardiomyopathy (HCM), postviral myocardial fibrosis (PVMF), and systemic sclerosis associated primary heart involvement (SSc-pHI). CODEX-based protein imaging provided orthogonal support for cell subpopulations and cellular neighborhoods. Spatially informed clustering identified six Fb subpopulations: COL1A1hi/POSTNhi, NOTCH3+, TIMP1hi, GSNhi/DCNhi, AP1hi Fbs, and myofibroblasts. COL1A1hi/POSTNhi and NOTCH3+ Fbs were enriched in AMI, whereas GSNhi/DCNhi Fbs and myofibroblasts predominated in chronic fibrotic remodeling. These subpopulations displayed distinct extracellular matrix, inflammatory, and vasoregulatory programs. Infarction-associated reparative niches were enriched in COL1A1hi/POSTNhi or NOTCH3+ Fbs and SPP1+ or APOE+ macrophages (M{Phi}), whereas chronic fibroinflammatory niches were enriched in GSNhi/DCNhi or AP1hi Fbs or myofibroblasts with C1Q+ M{Phi} and plasma cells. The GSNhi/DCNhi Fb niche marked areas of subendocardial fibrosis, whereas the AP1hi Fb niche localized to perivascular fibrosis. In SSc-pHI, the actively fibrogenic COL1A1hi/POSTNhi Fb state characteristic of infarct scar formation was present at higher frequency than in other chronic entities and was individually associated with cardiac dysfunction, whereas the chronic GSNhi/DCNhi Fb niche was associated with the extent of interstitial fibrosis and anti-topoisomerase I autoantibodies. These data show that human myocardial fibrosis is organized into spatially distinct Fb subpopulations that assemble into context-specific fibroinflammatory niches across chronic fibrotic remodeling and repair after AMI.
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BibTeX
@misc{micu2026spatial,
title = {{Spatial organization of fibroblast subpopulations and niches across acute repair and chronic fibrotic remodeling of the human myocardium}},
author = {A. Micu and A.-E. Matei and Y.-N. Li and A.-C. Pecher and T. Filla and P.-M. Bruch and S. Dietrich and J. Henes and E. Zweck and M. Eckstein and K. Klingel and J. H. W. Distler and A.-H. Györfi},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.756898},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.756898v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Spatial organization of fibroblast subpopulations and niches across acute repair and chronic fibrotic remodeling of the human myocardium
AU - A. Micu
AU - A.-E. Matei
AU - Y.-N. Li
AU - A.-C. Pecher
AU - T. Filla
AU - P.-M. Bruch
AU - S. Dietrich
AU - J. Henes
AU - E. Zweck
AU - M. Eckstein
AU - K. Klingel
AU - J. H. W. Distler
AU - A.-H. Györfi
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.756898
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.756898v1
AB - Myocardial fibrosis is a common end point of acute and chronic cardiovascular injury, yet the spatially organized fibroblast (Fb) and immune-cell states that sustain fibrotic remodeling across etiologies remain incompletely defined. We applied cyclic in situ hybridization (cISH)-based spatial transcriptomics to myocardial biopsies from patients with acute myocardial infarction (AMI), ischemic cardiomyopathy (ICM), hypertrophic cardiomyopathy (HCM), postviral myocardial fibrosis (PVMF), and systemic sclerosis associated primary heart involvement (SSc-pHI). CODEX-based protein imaging provided orthogonal support for cell subpopulations and cellular neighborhoods. Spatially informed clustering identified six Fb subpopulations: COL1A1hi/POSTNhi, NOTCH3+, TIMP1hi, GSNhi/DCNhi, AP1hi Fbs, and myofibroblasts. COL1A1hi/POSTNhi and NOTCH3+ Fbs were enriched in AMI, whereas GSNhi/DCNhi Fbs and myofibroblasts predominated in chronic fibrotic remodeling. These subpopulations displayed distinct extracellular matrix, inflammatory, and vasoregulatory programs. Infarction-associated reparative niches were enriched in COL1A1hi/POSTNhi or NOTCH3+ Fbs and SPP1+ or APOE+ macrophages (M{Phi}), whereas chronic fibroinflammatory niches were enriched in GSNhi/DCNhi or AP1hi Fbs or myofibroblasts with C1Q+ M{Phi} and plasma cells. The GSNhi/DCNhi Fb niche marked areas of subendocardial fibrosis, whereas the AP1hi Fb niche localized to perivascular fibrosis. In SSc-pHI, the actively fibrogenic COL1A1hi/POSTNhi Fb state characteristic of infarct scar formation was present at higher frequency than in other chronic entities and was individually associated with cardiac dysfunction, whereas the chronic GSNhi/DCNhi Fb niche was associated with the extent of interstitial fibrosis and anti-topoisomerase I autoantibodies. These data show that human myocardial fibrosis is organized into spatially distinct Fb subpopulations that assemble into context-specific fibroinflammatory niches across chronic fibrotic remodeling and repair after AMI.
ER -