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CCR2 macrophage response determines the functional outcome following cardiomyocyte transplantation.
- Source :
- Genome Medicine; 8/10/2023, Vol. 15 Issue 1, p1-18, 18p
- Publication Year :
- 2023
-
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 Rag2<superscript>del</superscript> 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, Rag2<superscript>del</superscript> 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<superscript>−</superscript>MHC-II<superscript>lo</superscript> 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 1756994X
- Volume :
- 15
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Genome Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 169870985
- Full Text :
- https://doi.org/10.1186/s13073-023-01213-3