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.
Fields of science
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme