DS0403 -

Adipose tissue Hematopoiesis bridging ischemic heart disease and diabetes – WAT-HEART

Submission summary

Cardiovascular diseases (CVD), including ischemic heart disease (IHD), are the main cause of mortality in nearly all European Union member states, accounting for almost 40% of all deaths in the region in 2011. In particular, the cardiovascular risk in people with diabetes mellitus is two to three times higher than in those without the disease and CVD. This situation clearly calls for the absolute necessity to pursue basic and translational research in order to progress beyond state-of-the-art, identify and test new strategies to limit CVD especially in patients experiencing type 2 diabetes (T2D). Emerging evidences suggest that myeloid-derived cells may provide the necessary signals to drive both cardiogenesis and tissue remodeling. In response to acute myocardial infarction (AMI), different subpopulations of myeloid cells, such as monocytes, macrophages and mast cells are recruited in the infarcted heart and participate to cardiac repair and remodeling. On T2D background, monocytes, macrophages as well as mast cells fate switches towards an inflammatory phenotype that could precipitate adverse ventricular remodeling after AMI.
The classical paradigm indicates that recruited myeloid-derived cells populating the ischemic heart mainly derive from genuine hematopoietic progenitors residing in the bone marrow (BM). Remarkably, recent works have challenged the view of medullary origin of hematopoiesis and found that systemic inflammation can also stimulate extramedullary hematopoiesis in adult mice and humans. First and foremost, pioneer work from partner 1 showed that WAT-stroma vascular fraction exhibits hematopoietic regenerative potential. Such WAT hematopoietic activity relies on the presence of a large population of hematopoietic stem/progenitor cells, producing 80 to 100% of mast cells and macrophages within WAT, but also in other organs. These original results suggest that, in addition to the BM, WAT constitutes an alternative source of innate immune cells that may contribute to inter-organ dialogue.
We thus hypothesize that beside metabolic and endocrine signals, WAT interacts with other organs via the production of myeloid cells, notably monocytes/macrophages and mast cells that participate to remodelling and/or regenerative processes in target organs. A dysfunction of WAT-hematopoiesis may lead to adverse effects on these processes. In parallel, WAT-hematopoietic activity is controlled by external signals from injured tissues, and in turn controls the WAT physiology itself.
In line with this hypothesis, preliminary results obtained by the consortium suggest that WAT-derived myeloid cells are able to home to the cardiac tissue where they can participate to regenerative and/or reparative processes. In addition, a dysfunction of WAT-hematopoiesis is observed T2D, and plays a pivotal and causative role in the development of the disease.
The main objectives of this project are to demonstrate that (i) immune cells contributing to cardiac remodeling after AMI partly derive from WAT, (ii) diabetes–induced dysfunction of WAT hematopoiesis contributes to alteration in cardiac remodeling and (iii) the WAT-hematopoietic activity depends on signals from the infarcted heart.
Hence, the major conceptual breakthrough of the present project implies a switch in the conceptual archetype depicting the origin of myeloid cells and our major objective is to establish proof of concept of this hypothesis, emphasizing the intrinsic crosstalk between WAT-derived myeloid cells and the cardiac homeostasis. Gain of knowledge in this novel and unexpected function of the WAT could lead to identify innovative therapeutic targets to prevent or treat IHD associated with diabetes.

Project coordination

Béatrice Cousin (Centre National de la Recherche Scientifique/STROMALab)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


CNRS/STROMALab Centre National de la Recherche Scientifique/STROMALab
Inserm UMRS 970 Institut National de la santé et de la recherche médicale

Help of the ANR 449,883 euros
Beginning and duration of the scientific project: September 2016 - 36 Months

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