Comparison of scRNA-seq data using OrthoIntegrate revealed that 54% of genes were commonly regulated between human HFrEF and a mouse chronic infarction model, with unique pathways in humans.
The OrthoIntegrate pipeline reveals that while human HFrEF and mouse models share 54% of regulated genes, unique human-specific pathways like angiogenesis highlight limitations in the translational comparability of mouse models.
BACKGROUND: Cardiovascular research heavily relies on mouse (Mus musculus) models to study disease mechanisms and to test novel biomarkers and medications. Yet, applying these results to patients remains a major challenge and often results in noneffective drugs. Therefore, it is an open challenge of translational science to develop models with high similarities and predictive value. This requires a comparison of disease models in mice with diseased tissue derived from humans. RESULTS: To compare the transcriptional signatures at single-cell resolution, we implemented an integration pipeline called OrthoIntegrate, which uniquely assigns orthologs and therewith merges single-cell RNA sequencing (scRNA-seq) RNA of different species. The pipeline has been designed to be as easy to use and is fully integrable in the standard Seurat workflow.We applied OrthoIntegrate on scRNA-seq from cardiac tissue of heart failure patients with reduced ejection fraction (HFrEF) and scRNA-seq from the mice after chronic infarction, which is a commonly used mouse model to mimic HFrEF. We discovered shared and distinct regulatory pathways between human HFrEF patients and the corresponding mouse model. Overall, 54% of genes were commonly regulated, including major changes in cardiomyocyte energy metabolism. However, several regulatory pathways (e.g., angiogenesis) were specifically regulated in humans. CONCLUSIONS: The demonstration of unique pathways occurring in humans indicates limitations on the comparability between mice models and human HFrEF and shows that results from the mice model should be validated carefully. OrthoIntegrate is publicly accessible (https://github.com/MarianoRuzJurado/OrthoIntegrate) and can be used to integrate other large datasets to provide a general comparison of models with patient data.
Jurado et al. (Mon,) conducted a other in Heart failure with reduced ejection fraction (HFrEF). Human HFrEF scRNA-seq vs. Mouse chronic infarction scRNA-seq was evaluated on Commonly regulated genes. Comparison of scRNA-seq data using OrthoIntegrate revealed that 54% of genes were commonly regulated between human HFrEF and a mouse chronic infarction model, with unique pathways in humans.