Work

Spatial organization of fibroblast subpopulations and niches across acute repair and chronic fibrotic remodeling of the human myocardium

Year: 2026

Type: preprint

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: COL1A1 hi /POSTN hi , NOTCH3 + , TIMP1 hi , GSN hi /DCN hi , AP1 hi Fbs, and myofibroblasts. COL1A1 hi /POSTN hi and NOTCH3 + Fbs were enriched in AMI, whereas GSN hi /DCN hi 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 COL1A1 hi /POSTN hi or NOTCH3 + Fbs and SPP1 + or APOE + macrophages (MФ), whereas chronic fibroinflammatory niches were enriched in GSN hi /DCN hi or AP1 hi Fbs or myofibroblasts with C1Q + MФ and plasma cells. The GSN hi /DCN hi Fb niche marked areas of subendocardial fibrosis, whereas the AP1 hi Fb niche localized to perivascular fibrosis. In SSc-pHI, the actively fibrogenic COL1A1 hi /POSTN hi 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 GSN hi /DCN hi 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. What Is New? Spatially resolved single-cell transcriptomics of myocardial biopsies from acute myocardial infarction, ischemic and hypertrophic cardiomyopathy, postviral myocardial fibrosis, and systemic sclerosis-associated primary heart involvement (SSc-pHI) resolves six fibroblast subpopulations assembling into context-specific fibroinflammatory niches. Infarct scar formation and chronic fibrotic remodeling are organized by distinct fibroblast-macrophage circuits: COL1A1 hi /POSTN hi and NOTCH3 + fibroblasts with SPP1 + macrophages in infarct scar, versus GSN hi /DCN hi and AP1 hi fibroblasts with C1Q + macrophages and plasma cells in chronic disease. Subendocardial fibrosis maps onto GSN hi /DCN hi and perivascular fibrosis onto AP1hi neighborhoods. SSc-pHI is distinguished by increased actively fibrogenic COL1A1 hi /POSTN hi fibroblasts, transient during infarct scar formation, indicating ongoing fibrogenesis. What Are the Clinical Implications? Spatial profiling links histological patterns of myocardial fibrosis to distinct fibroblast and immune-cell environments, providing a basis for investigating how these cellular relationships contribute to myocardial remodeling. In SSc-pHI, infarct scar-associated COL1A1 hi /POSTN hi fibroblasts occur alongside GSN hi /DCN hi fibroblasts. These findings provide a basis for functional and longitudinal studies to define their contributions to myocardial remodeling and evaluate their potential as markers of disease activity or therapeutic targets. Prospective studies integrating these tissue findings with cardiac imaging and circulating biomarkers should establish whether the observed cellular patterns provide additional information about disease progression or treatment response.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.06.756898