Multi-Omics Integration Reveals Incomplete Reactivation of Developmental Cell-Cycle Programs in Adult Human Infarcted Hearts.
Only about 5% of cardiomyocytes can re-enter the cell cycle after heart damage, but they fail to complete division due to insufficient activation of necessary genes.
Where it sits
this study against the rest of the igf-1 des (des(1-3) igf-1) corpusSummary and findings
This study investigates the reactivation of developmental cell-cycle programs in adult human hearts after myocardial infarction, focusing on cardiomyocytes. The research utilized multi-omics approaches to analyze gene expression and chromatin accessibility in both human fetal and adult infarcted hearts. No therapeutic claims are made.
Abstract
Adult human hearts show limited regeneration after acute myocardial infarction (AMI) despite a small subpopulation (~5%) of cardiomyocytes re-entering the cell cycle. We integrated public single-nucleus RNA-seq, spatial transcriptomics, bulk RNA-seq and ATAC-seq datasets from human fetal hearts and adult infarcted hearts to investigate why cell-cycle-active cardiomyocytes fail to complete division. These cells were enriched in the infarct zone (IZ) and activated early cell-cycle programs, but showed insufficient reactivation of late mitotic and cytokinesis execution machinery, particularly ANLN and KIF18A, and instead engaged stress-adaptive programs. Multi-omics filtering across expression, chromatin accessibility, and co-expression/regulatory networks highlighted five developmental cell-cycle-associated genes with insufficient adult reactivation: ANLN, KIF18A, MDK, RTKN2, and SOX11. In human induced pluripotent stem cell-derived cardiomyocytes, hypoxia suppressed most candidates, whereas MDK retained responsiveness to pro-proliferative Wnt stimulation. These findings suggest that incomplete cytokinesis reactivation represents a key bottleneck for adult human cardiac regeneration, and nominate MDK as a tractable candidate for chemical biology and drug-discovery efforts aimed at promoting cardiomyocyte cell-cycle completion.
Background
This paper addresses the biological question of how developmental cell-cycle programs are reactivated in adult human hearts following infarction. Previous research has indicated that such reactivation may be crucial for cardiac repair and regeneration. Understanding these mechanisms could provide insights into potential therapeutic strategies for heart disease.
Methods
The study employed a multi-omics integration approach to analyze heart tissue samples from adult humans who experienced infarction. Specific details regarding the sample size, dosing, duration, and primary versus secondary outcome measures are not reported in the abstract.
Results
Not reported in abstract.
Interpretation
The findings of this study may contribute to the existing literature on cardiac regeneration, although the lack of specific numeric results limits the ability to assess the clinical significance of the findings. Without clear effect sizes or statistical analyses, it is difficult to draw strong conclusions regarding the implications for clinical practice.
Key findings
- Not reported in abstract.
Limitations
- Not reported in abstract.