Investigating the role of macrophages in the adaptive response of neonatal mice to pressure overload

Mohammed reda Djabour (Bonn)1, J. Nicke (Bonn)1, F. Ebach (Bonn)1, B. Fleischmann (Bonn)1, M. Malek Mohammadi (Bonn)1

1Universitätsklinikum Bonn Physiologie I Life & Brain Center Bonn, Deutschland


Introduction: Cardiovascular diseases are the leading cause of death worldwide. This is mainly due to insufficient regenerative ability and low cardiomyocyte renewal rate in the adult heart. In contrast, the neonatal mammalian heart has the ability to regenerate. This regeneration process is known to be orchestrated through interaction of many cell types, such as immune cells, which leads to enhanced cardiomyocytes proliferation and angiogenesis. A study from our group showed that the neonatal mouse heart at postnatal day 0 (P0) is also able to adapt to pressure overload (POL). This adaptive response was characterized by preserved cardiac function, enhanced cardiomyocyte proliferation and angiogenesis in the absence of interstitial fibrosis or cardiac hypertrophy. This ability, however, is lost at P7 and POL leads to cardiomyocyte hypertrophy, interstitial fibrosis and impaired cardiac function. Transcriptomics analysis has shown major differences in the immune response of P0 compared to P7 injured hearts. The immune response in P0 appeared to be related to innate immunity, while in P7 was more inflammatory. Since macrophages are the main cells of innate immunity and those originating from the embryonic phase, especially from the yolk-sac can have pro-regenerative and pro-angiogenic properties, we hypothesized that embryonic macrophages at P0 can play a role in the adaptive response of the heart to POL.   

Method: To investigate the immune response of neonatal mice to POL we performing neonatal model of transverse aortic constriction (nTAC) at P0 or P7 and the hearts were harvested 7 and 14 days after injury. No-injured hearts were also collected at P0, P7 and P14 as controls. In order to assess macrophages in the heart, immunofluorescence staining was performed against general (F4/80) and embryonic macrophage markers (TIM4 and LYVE1).

Results: Quantification of macrophages in the non-injured postnatal hearts revealed decreased number of total macrophages with age from P0-P14 in the hearts. This number, however, was not reduced and even increased at P14 upon induction of pressure overload at P0. The decrease of macrophages with age was more pronounced when it came to an embryonic subpopulation of macrophages (TIM4+F4/80+). However, this subpopulation also increased in response to POL at P0. Assessing the hearts upon induction of POL at P7 indicated an increase in total number of macrophages, which appeared to consist of a different subpopulation (LYVE1- F4/80+). LYVE1+ macrophages also showed a different pattern upon P0 compared to P7 injury.  

Conclusion: These data indicated that macrophages and their subpopulations in the heart change with age during postnatal development, which can explain different immune responses of P0 compared to P7 hearts to injury. These differences in immune response and macrophage subpopulations could potentially contribute to the regenerative ability of P0 and lack of it in P7 mice. We will further investigate macrophage subpopulations and their response to POL at P0 and P7 using flow cytometry analysis. In addition, to understand the contribution and role of embryonic macrophages to the adaptive response of the P0 heart and lack of it in P7, we will perform lineage tracing of different macrophage subpopulations upon nTAC using transgenic mouse models.

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