%0 Journal Article %1 d794189948e74d74982cbaceea556372 %A Vasudevan, Praveen %A Wolfien, Markus %A Lemcke, Heiko %A Lang, Cajetan Immanuel %A Skorska, Anna %A Gaebel, Ralf %A Galow, Anne-Marie %A Koczan, Dirk %A Lindner, Tobias %A Bergmann, Wendy %A Mueller-Hilke, Brigitte %A Vollmar, Brigitte %A Krause, Bernd Joachim %A Wolkenhauer, Olaf %A Steinhoff, Gustav %A David, Robert %D 2023 %I BioMed Central, London %J Genome medicine %K topic_lifescience Animals, C57BL, Cardiac/metabolism, Cell FIS_scads Immunocompromised, Inbred Infarction, Machine Macrophages, Macrophages/metabolism, Mice, Monocytes/metabolism Myocardial Myocytes, Single-cell, infarction, learning, therapy, %N 1 %R 10.1186/s13073-023-01213-3 %T CCR2 macrophage response determines the functional outcome following cardiomyocyte transplantation %V 15 %X BACKGROUND: The immune response is a crucial factor for mediating the benefit of cardiac cell therapies. Our previous research showed that cardiomyocyte transplantation alters the cardiac immune response and, when combined with short-term pharmacological CCR2 inhibition, resulted in diminished functional benefit. However, the specific role of innate immune cells, especially CCR2 macrophages on the outcome of cardiomyocyte transplantation, is unclear.METHODS: We compared the cellular, molecular, and functional outcome following cardiomyocyte transplantation in wildtype and T cell- and B cell-deficient Rag2del mice. The cardiac inflammatory response was assessed using flow cytometry. Gene expression profile was assessed using single-cell and bulk RNA sequencing. Cardiac function and morphology were determined using magnetic resonance tomography and immunohistochemistry respectively.RESULTS: Compared to wildtype mice, Rag2del mice show an increased innate immune response at steady state and disparate macrophage response after MI. Subsequent single-cell analyses after MI showed differences in macrophage development and a lower prevalence of CCR2 expressing macrophages. Cardiomyocyte transplantation increased NK cells and monocytes, while reducing CCR2-MHC-IIlo macrophages. Consequently, it led to increased mRNA levels of genes involved in extracellular remodelling, poor graft survival, and no functional improvement. Using machine learning-based feature selection, Mfge8 and Ccl7 were identified as the primary targets underlying these effects in the heart.CONCLUSIONS: Our results demonstrate that the improved functional outcome following cardiomyocyte transplantation is dependent on a specific CCR2 macrophage response. This work highlights the need to study the role of the immune response for cardiomyocyte cell therapy for successful clinical translation.

@article{d794189948e74d74982cbaceea556372, abstract = {BACKGROUND: The immune response is a crucial factor for mediating the benefit of cardiac cell therapies. Our previous research showed that cardiomyocyte transplantation alters the cardiac immune response and, when combined with short-term pharmacological CCR2 inhibition, resulted in diminished functional benefit. However, the specific role of innate immune cells, especially CCR2 macrophages on the outcome of cardiomyocyte transplantation, is unclear.METHODS: We compared the cellular, molecular, and functional outcome following cardiomyocyte transplantation in wildtype and T cell- and B cell-deficient Rag2del mice. The cardiac inflammatory response was assessed using flow cytometry. Gene expression profile was assessed using single-cell and bulk RNA sequencing. Cardiac function and morphology were determined using magnetic resonance tomography and immunohistochemistry respectively.RESULTS: Compared to wildtype mice, Rag2del mice show an increased innate immune response at steady state and disparate macrophage response after MI. Subsequent single-cell analyses after MI showed differences in macrophage development and a lower prevalence of CCR2 expressing macrophages. Cardiomyocyte transplantation increased NK cells and monocytes, while reducing CCR2-MHC-IIlo macrophages. Consequently, it led to increased mRNA levels of genes involved in extracellular remodelling, poor graft survival, and no functional improvement. Using machine learning-based feature selection, Mfge8 and Ccl7 were identified as the primary targets underlying these effects in the heart.CONCLUSIONS: Our results demonstrate that the improved functional outcome following cardiomyocyte transplantation is dependent on a specific CCR2 macrophage response. This work highlights the need to study the role of the immune response for cardiomyocyte cell therapy for successful clinical translation.}, added-at = {2024-11-28T16:27:18.000+0100}, author = {Vasudevan, Praveen and Wolfien, Markus and Lemcke, Heiko and Lang, {Cajetan Immanuel} and Skorska, Anna and Gaebel, Ralf and Galow, Anne-Marie and Koczan, Dirk and Lindner, Tobias and Bergmann, Wendy and Mueller-Hilke, Brigitte and Vollmar, Brigitte and Krause, {Bernd Joachim} and Wolkenhauer, Olaf and Steinhoff, Gustav and David, Robert}, biburl = {https://puma.scadsai.uni-leipzig.de/bibtex/29a1b18045dd99caf7d58385620549516/scadsfct}, day = 10, doi = {10.1186/s13073-023-01213-3}, interhash = {6fc044457d368f713da7f774fddd5b93}, intrahash = {9a1b18045dd99caf7d58385620549516}, issn = {1756-994X}, journal = {Genome medicine}, keywords = {topic_lifescience Animals, C57BL, Cardiac/metabolism, Cell FIS_scads Immunocompromised, Inbred Infarction, Machine Macrophages, Macrophages/metabolism, Mice, Monocytes/metabolism Myocardial Myocytes, Single-cell, infarction, learning, therapy,}, language = {English}, month = aug, note = {Publisher Copyright: {\textcopyright} 2023, BioMed Central Ltd., part of Springer Nature.}, number = 1, publisher = {BioMed Central, London}, timestamp = {2024-11-28T17:41:31.000+0100}, title = {CCR2 macrophage response determines the functional outcome following cardiomyocyte transplantation}, volume = 15, year = 2023 }