Atlas of 24 human hearts finds FB_c1 fibroblast subpopulation and candidate regulators of cardiac fibrosis

Researchers have built a single-cell atlas of human cardiomyopathic hearts and identified an activated fibroblast subpopulation, FB_c1, associated with cardiac fibrosis, according to a study in the Journal of Translational Medicine. The analysis used single-cell RNA sequencing data from 24 human heart samples: 4 normal and 20 diseased biomedcentral.comJournal of Translational Medicinebiomedcentral.comOpen source ↗. Cardiomyopathy is a principal cause of heart failure worldwide, and pathological fibrosis, driven mainly by activated fibroblasts, is central to its progression.

The authors note that the cellular heterogeneity and the exact molecular mechanisms of fibrotic remodelling remain inadequately understood, which limits the development of targeted therapies.

Data and methods

The single-cell data were integrated with genome-wide association study summary statistics and bulk transcriptomic datasets. The analytical framework included construction of the cellular atlas, Single-cell Disease Relevance Score (scDRS) and Augur perturbation analyses, and protein-protein interaction networks. It also included pseudotime trajectory inference, regulatory network analysis with SCENIC, and in silico gene knockout modelling with scTenifoldKnk.

Fibroblasts, LUM and PLAGL1

Diseased hearts showed enrichment of immune cells and the FB_c1 fibroblast subpopulation. FB_c1 was enriched in both ischaemic and dilated cardiomyopathy and showed elevated expression of extracellular matrix (ECM) genes biomedcentral.comJournal of Translational Medicinebiomedcentral.comOpen source ↗. The scDRS and Augur analyses identified fibroblasts as a disease-associated cell population linked to the genetic risk of heart failure and to transcriptional perturbation.

Multicohort transcriptomic analysis and protein-protein interaction prioritisation highlighted LUM as a fibrosis-associated ECM candidate gene. Pseudotime analysis suggests a transcriptional continuum of fibroblast activation rather than a definitive lineage progression.

Regulatory network analysis, in silico perturbation and PLAGL1 knockdown experiments support PLAGL1 as a candidate regulator associated with fibroblast activation and ECM remodelling.

Limits of the findings

The authors describe FB_c1 as a disease-associated activated fibroblast state. PLAGL1 and LUM, they state, should be interpreted as candidate regulators or markers. Further spatial, functional and in vivo validation is required before causal or translational roles can be established biomedcentral.comJournal of Translational Medicinebiomedcentral.comOpen source ↗.