%0 Journal Article %1 Vasudevan2023-zx %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 %J Genome Med. %K Cell Immunocompromised; Machine Macrophages; Myocardial Single-cell infarction; learning; therapy; topic_lifescience %N 1 %P 61 %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{Vasudevan2023-zx, 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 = {2024-09-10T10:41:24.000+0200}, 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/224f00e5014ba844d1303b875d8d56e42/scadsfct}, interhash = {6fc044457d368f713da7f774fddd5b93}, intrahash = {24f00e5014ba844d1303b875d8d56e42}, journal = {Genome Med.}, keywords = {Cell Immunocompromised; Machine Macrophages; Myocardial Single-cell infarction; learning; therapy; topic_lifescience}, language = {en}, month = aug, number = 1, pages = 61, timestamp = {2024-09-10T12:00:15.000+0200}, title = {{CCR2} macrophage response determines the functional outcome following cardiomyocyte transplantation}, volume = 15, year = 2023 }