Disparate immune responses lead to varied outcomes following cardiomyocyte transplantation

Aims: The immune response is important for mediating the benefit of cardiac cell therapies. The role of varied immune responses in influencing the outcome of cardiomyocyte cell transplantation after myocardial infarction was investigated. Methods and Results: Cardiac flow cytometric analysis of C57BL/6J and T- and B cell deficient Rag2del mice revealed varied CD11b, natural killer and dendritic cell responses following sham injection and a disparate macrophage response after myocardial infarction. Subsequent single-cell analysis showed similar clusters of various immune cells with a heterogeneous gene expression profile between the mice and a higher prevalence of CCR2 expressing macrophages in C57BL/6J mice. Cardiomyocyte transplantation after MI reduced the percentage of CCR2-MHC-IIlo macrophages and showed no significant functional improvement in Rag2del mice, while improving left ventricular ejection fraction, end systolic volume and lateral wall thickness in C57BL/6J mice. Transcriptome analysis showed changes in extracellular remodelling and immune response processes in Rag2del mice potentially explaining the contrasting functional outcomes. Using machine learning based feature selection, Mfge8 and Ccl7 were identified as the primary effector targets of cardiomyocyte transplantation in the heart. Conclusion: This work shows the major differences in CCR2 macrophage response after myocardial infarction between C57BL/6J and immunocompromised Rag2del mice at a single cell resolution. Moreover, these differences also influence the functional outcome following cardiomyocyte transplantation, the most important targets of which were identified using machine learning. Importantly, these findings reveal the need to consider the immune response in future studies for cardiomyocyte transplantation.