StellateZEN · Unravelling the crosstalk between Stellate cells and Kupffer cells and its role in maintaining Stellate cell quiescence
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2022-06-01 → 2024-12-31
- EU contribution
- €175,920
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
Unravelling the crosstalk between Stellate cells and Kupffer cells and its role in maintaining Stellate cell quiescence
Chronic liver diseases account for two million deaths a year, half of which can be attributed to liver fibrosis. The later stage of fibrosis, cirrhosis, leads to serious complications such as liver failure, portal hypertension, and represents a risk factor for developing hepatocellular carcinoma. Chronic liver disease can have multiple causes: alcohol, viral hepatitis, metabolic-associated fatty liver disease or drug induced liver injury. Independent of the etiology, activated hepatic stellate cells are the major source of excessive extracellular-matrix deposition that drives fibrosis. An increasing body of evidence suggest that upon resolution of liver inflammation, activated stellate cells can either undergo senescence, apoptosis, or revert to quiescence (i.e. homeostasis, unactivated). Hence, understanding molecular mechanisms driving and maintaining stellate cell quiescence is key and could potentially lead to novel fibrosis treatments. Stellate cells are liver stromal cells that are in close contact with hepatocytes, liver sinusoidal endothelial cells and resident macrophages of the liver, the Kupffer cells (KCs). Recent studies have highlighted the important crosstalk between KCs and stellate cells. Our group showed that at steady state, they are always paired with one another. Moreover, upon KC depletion, stellate cells attract monocytes and promote their differentiation into KCs, highlighting the interconnectivity of these cells. A crucial part of this process is the BMP9/ALK1 signaling axis. In the liver stellate cells are the only source of BMP9 whilst KCs express the receptor ALK1. Importantly, while quiescent stellate cells are always paired with KCs, several studies have reported that profibrogenic activated stellate cells are instead paired with inflammatory macrophages. This suggests that stellate cell micro-environment forms a niche providing signals that imprint their identity and/or function. In this project, our overall objective is to decipher stellate cell niche to understand which signals are important to drive and maintain their quiescent identity. This study aims at investigating the crosstalk between stellate cells and KCs in the liver.
Data: CORDIS, © European Union
Project objective
Liver diseases are a global cause of mortality, accounting for two million deaths a year, of which half are attributed to liver fibrosis. Activated stellate cells are the major source of excessive extracellular-matrix deposition that drives fibrosis. The signals that convert quiescent stellate cells into pathogenic myofibroblasts remain largely unknown. Spatial analysis from the Guilliams lab has recently revealed that each quiescent stellate cell is paired with a Kupffer cell (KC) in the steady-state liver. This is because stellate cells play a central role in the maintenance of the KC pool. Indeed, upon KC depletion, stellate cells are the main cells promoting the recruitment of monocytes and their differentiation into KCs through the production of instructive signals. Interestingly, in fibrotic livers of mice and humans the progressive activation of stellate cells is coupled with the gradual disappearance of KCs and pro-fibrotic stellate cells are no longer paired with KCs. I hypothesize that the KC-Stellate cell relationship is mutually beneficial and essential for liver homeostasis and that, just as the stellate cell is the primary cell of the KC niche, KCs play a key role in preventing stellate cell activation. I have recently identified a mouse model in which the knock-down of a receptor for one of the main stellate cell-derived instructive factors leads to an almost complete absence of KCs in the liver. This yields a liver where most stellate cells are not paired with a KC. Interestingly, these mice spontaneously develop fibrosis, strengthening my hypothesis that KCs are crucial to maintain stellate cells quiescence. In this project, I will use scRNA-seq and spatial transcriptomics to study stellate cells paired or unpaired with a KC to define and study gene targets involved in the KC-stellate cell crosstalk, in the hope to unravel the KC-derived signals that maintain stellate cells in a quiescent state, as this may lead to novel anti-fibrotic strategies.
Original text from CORDIS.
Participants
- VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium
Links
Data: CORDIS, © European Union