CCR2 macrophage response determines the functional outcome following cardiomyocyte transplantation

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Praveen Vasudevan - , Universitätsmedizin Rostock (Autor:in)
  • Markus Wolfien - , Institut für Medizinische Informatik und Biometrie, Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI Dresden), Universität Rostock (Autor:in)
  • Heiko Lemcke - , Universitätsmedizin Rostock (Autor:in)
  • Cajetan Immanuel Lang - , Universitätsmedizin Rostock (Autor:in)
  • Anna Skorska - , Universitätsmedizin Rostock (Autor:in)
  • Ralf Gaebel - , Universitätsmedizin Rostock (Autor:in)
  • Anne-Marie Galow - , Institute of Genome Biology (Autor:in)
  • Dirk Koczan - , Universitätsmedizin Rostock (Autor:in)
  • Tobias Lindner - , Core Facility Multimodal Small Animal Imaging, Universitätsmedizin Rostock (Autor:in)
  • Wendy Bergmann - , Universitätsmedizin Rostock (Autor:in)
  • Brigitte Mueller-Hilke - , Universitätsmedizin Rostock (Autor:in)
  • Brigitte Vollmar - , Universitätsmedizin Rostock (Autor:in)
  • Bernd Joachim Krause - , Universitätsmedizin Rostock (Autor:in)
  • Olaf Wolkenhauer - , Universitätsmedizin Rostock (Autor:in)
  • Gustav Steinhoff - , Universitätsmedizin Rostock (Autor:in)
  • Robert David - , Universitätsmedizin Rostock (Autor:in)

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.

Details

OriginalspracheEnglisch
Aufsatznummer61
Seitenumfang1
FachzeitschriftGenome medicine
Jahrgang15
Ausgabenummer1
PublikationsstatusVeröffentlicht - 10 Aug. 2023
Peer-Review-StatusJa

Externe IDs

Scopus 85167651668
Mendeley 7438b2f7-d2dd-37fe-aeb5-d792b429e516
ORCID /0000-0002-1887-4772/work/143075281

Schlagworte

Fächergruppen, Lehr- und Forschungsbereiche, Fachgebiete nach Destatis

Schlagwörter

  • Cell therapy, Immunocompromised, Machine learning, Macrophages, Myocardial infarction, Single-cell, Myocytes, Cardiac/metabolism, Macrophages/metabolism, Mice, Inbred C57BL, Myocardial Infarction, Animals, Mice, Monocytes/metabolism

Bibliotheksschlagworte