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Determining the instructive tissue signals and the master transcription factors driving Kupffer cell differentiation

Periodic Reporting for period 2 - KupfferCellNiche (Determining the instructive tissue signals and the master transcription factors driving Kupffer cell differentiation)

Reporting period: 2019-01-01 to 2020-06-30

Macrophages are immune cells that can be found in all organs. We had demonstrated that macrophages develop before birth from newly identified embryonic precursors that seed the tissues before birth, acquire a unique tissue-specific functional specialization in each organ and then self-maintain throughout life without any contribution from circulating adult precursors such as monocytes. However, we have very recently found that when adult monocytes get access to the empty macrophage niche in the liver or the lung they acquire identical tissue-specific macrophage functions and self-maintenance capacities as macrophages of embryonic origin. This paves the way towards monocyte-based cellular therapy in diseases associated with macrophage dysfunction. This includes a disease known as pulmonary alveolar proteinosis that develops in patients in which macrophages fail to clear surfactant proteins in the lungs. Using a mouse model, we have demonstrated that a single transfer of monocytes can cure this rare disease. This ERC grant aims at identifying the tissue-derived factors that imprint a unique functional specialization in each organ and provide the self-maintenance capacity to macrophages. This knowledge should permit the development of novel therapies for diseases in which macrophages play a central role.
The finding we are most proud of is that we revealed that macrophages develop together with their organ of residence in the embryo and take on a unique functional specialization that is crucial for the day-to-day function of each organ. We proposed that there would be a restricted number of macrophage “niches” per organ imprinting these unique functions and generated the first transgenic tools specific for liver macrophages known as Kupffer cells to unravel the molecular mechanisms underlying the liver-specific imprinting. The search for the Kupffer cell niche led us to solve a 100 year old mystery. Dr. Karl von Kupffer first identified “Sternzellen” by gold chloride staining and later proposed that these cells were macrophages because he found cells phagocytosing inkt particles with a similar distribution in the liver. Later it became clear that we were dealing with two different cells: phagocytic Kupffer cells now known to be macrophages and gold chloride stained Stellate cells now known to be pericytes. This year we have revealed that the reason Karl von Kupffer confused both cells is that the Stellate cell is an essential part of the Kupffer cell niche and that both cells are always found in pairs across an endothelial cell. Moreover, we identified the stellate and endothelial cell derived molecules that imprint the unique Kupffer cell identity and functional specialization.
We will now study the cell-cell circuits present in the human liver through our contribution the Human Cell Atlas consortium: https://chanzuckerberg.com/science/programs-resources/humancellatlas/seednetworks/a-reference-cell-atlas-of-human-liver-diversity-over-a-lifespan/. We have already found that the main transcription factors identified through this ERC are conserved in liver macrophages across 5 species. This emphasizes the translational aspect of our research. By the end of this project we want to identify the main signals driving these transcription factors and understand how they imprint the liver-specific identity and contribute to liver homeostasis.