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Modulating neutrophil phenotype via mesenchymal stromal cell paracrine signals; insights from human and mouse experiments

ABSTRACT: Neutrophils play a central role in the inflammatory and reparative processes following myocardial infarction (MI), and can switch between pro-inflammatory (N1) and reparatory (N2) states, influencing disease outcomes. Mesenchymal stromal cells (MSC), known for their immunomodulatory effects, may hold the key to controlling neutrophil behaviour. In this study, we explored how MSC influence neutrophil states both in vitro and in vivo in an MI mouse model. We developed a reliable system to study neutrophils by differentiating HL-60 cells into neutrophil-like cells (dHL-60). These cells were polarized into N1 and N2 types, showing distinct protein markers and cytokine signatures. When exposed to MSC, pro-inflammatory N1 cells reduced their production of inflammatory signals (TNFα, MCP-1), while N2 cells increased their reparatory signals (IL-10, TGM2). In mice with MI, MSC reduced the number of neutrophils migrating to damaged heart tissue and altered their transcriptomic signatures. Surprisingly, MSC enhanced inflammatory pathways in heart neutrophils while dampening their ability to support tissue repair. These findings underscore the complex role of MSC in modulating neutrophil responses, demonstrating a nuanced impact on inflammatory and reparative pathways in the cardiac microenvironment. While the results highlight MSC' potential to influence immune cell behaviour, they also reveal context-specific effects that warrant further investigation to fully elucidate their therapeutic implications in cardiovascular disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE287432 | GEO | 2025/08/15

REPOSITORIES: GEO

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Project description:Dunster2014 - WBC Interactions (Model1) This is a sub-model of a three-step inflammatory response modelling study. The model includes distinct populations of white blood cells namely, macrophages and active and apoptotic neutrophil populations. Neutrophil apoptosis rate is predicted to be crucial for the qualitative nature of the system. This model is described in the article: The resolution of inflammation: a mathematical model of neutrophil and macrophage interactions. Dunster JL, Byrne HM, King JR. Bull. Math. Biol. 2014 Aug; 76(8): 1953-1980 Abstract: There is growing interest in inflammation due to its involvement in many diverse medical conditions, including Alzheimer's disease, cancer, arthritis and asthma. The traditional view that resolution of inflammation is a passive process is now being superceded by an alternative hypothesis whereby its resolution is an active, anti-inflammatory process that can be manipulated therapeutically. This shift in mindset has stimulated a resurgence of interest in the biological mechanisms by which inflammation resolves. The anti-inflammatory processes central to the resolution of inflammation revolve around macrophages and are closely related to pro-inflammatory processes mediated by neutrophils and their ability to damage healthy tissue. We develop a spatially averaged model of inflammation centring on its resolution, accounting for populations of neutrophils and macrophages and incorporating both pro- and anti-inflammatory processes. Our ordinary differential equation model exhibits two outcomes that we relate to healthy and unhealthy states. We use bifurcation analysis to investigate how variation in the system parameters affects its outcome. We find that therapeutic manipulation of the rate of macrophage phagocytosis can aid in resolving inflammation but success is critically dependent on the rate of neutrophil apoptosis. Indeed our model predicts that an effective treatment protocol would take a dual approach, targeting macrophage phagocytosis alongside neutrophil apoptosis. This model is hosted on BioModels Database and identified by: BIOMD0000000616. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Modulating neutrophil phenotype via mesenchymal stromal cell paracrine signals; insights from human and mouse experiments

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