Periodic Reporting for period 1 - LiverMacRegenCircuit (Elucidating the role of macrophages in liver regeneration and tissue unit formation)
Periodo di rendicontazione: 2020-09-01 al 2022-08-31
The liver is a highly regenerative organ, able to efficiently restore mass and function following toxin, viral or surgically induced tissue damage, as long as the damage remains limited. However, with a growing incidence of persistent hepatitis infection, alcoholism and metabolic disorders, acute and chronic liver failure is becoming increasingly prevalent, associated with high morbidity and mortality. Currently, one of the main treatments for liver failure is transplantation, with more than 5,500 liver transplants occurring in Europe annually. However, the side effects of immunosuppression, cost and limited supplies of donor organs have prevented its broader application. As such, there is a desperate need for a greater understanding of the regeneration process and development of pro-regenerative therapies.
This project studies the cellular and molecular mechanisms driving liver regeneration. We will use single-cell sequencing and spatial transcriptomics to track the cell-cell interactions during liver regeneration. By better understanding the molecular mechanisms at play, we hope to pave the way towards novel therapeutic interventions that could boost liver regeneration in patients and prevent the need for liver transplantation.
The project has achieved most of its objectives and milestones for the period, with relatively minor deviations. We are finalizing the last part of WP4 for the moment. We are currently blocking one of the key cell-cell interactions we have identified to be increased specifically during liver regeneration. We believe this is part of a central liver regeneration program and are currently assessing the role of this program in liver regeneration. Our preliminary data are very promising and show an effect of regeneration but this needs to be repeated and further characterized. Once this is done we will be able to finalize our second publication for this project. We expect this to be ready within the next 6 months.
This project studies the cellular and molecular mechanisms driving liver regeneration. We will use single-cell sequencing and spatial transcriptomics to track the cell-cell interactions during liver regeneration. By better understanding the molecular mechanisms at play, we hope to pave the way towards novel therapeutic interventions that could boost liver regeneration in patients and prevent the need for liver transplantation.
The project has achieved most of its objectives and milestones for the period, with relatively minor deviations. We are finalizing the last part of WP4 for the moment. We are currently blocking one of the key cell-cell interactions we have identified to be increased specifically during liver regeneration. We believe this is part of a central liver regeneration program and are currently assessing the role of this program in liver regeneration. Our preliminary data are very promising and show an effect of regeneration but this needs to be repeated and further characterized. Once this is done we will be able to finalize our second publication for this project. We expect this to be ready within the next 6 months.
We have dissected the liver regeneration process and have followed the proliferation of the main liver cells in function of time. This reveals a step-wise proliferation of liver cells: first hepatocytes, then liver macrophages, then liver stellate cells and finally liver endothelial cells proliferate. Importantly, by the end of the week all these cells re-organise themselves properly so that the liver architecture of a healthy liver is obtained. This points towards a highly coordinated process. To track the spatial distribution of cellular proliferation in function of time we have developed novel spatial automated analysis methods based on machine-learning. This automated spatial analysis pipeline is already working for hepatocytes and is currently being tailored to also track the proliferation of myeloid, endothelial and mesenchymal cells in function of time. Importantly, this pipeline will also allow to track gene expression per celltype in function of time and space. There is currently a high demand for automated spatial analysis in the field. This is why we will study the possibility to generate a user-friendly algorithm that could be used by European biotech and pharma companies working on the liver. This could represent a major exploitation output of the current Marie-Curie program and once the automated spatial algorithm is finalized we will approach our TechTransfer team to see how we can best exploit it for industrial applications.
We have followed the changes in gene expression profile of the different cells in function of time and space during liver regeneration. To do so we had to develop novel spatial technologies such as spatial CITE-seq: this technology allows to measure both RNA expression and protein expression spatially. These protocols were developed in close collaboration with the company 10X Genomics and have resulted in the publication of the first Human Liver Cell Atlas across species. This was a massive project involving two labs: the Guilliams lab (focusing on the healthy liver) and the Scott lab (focusing on the fatty-liver). Freya Svedberg developed essential spatial protocols for this study and is therefore co-author on this publication:
Pubmed link to this article = https://pubmed.ncbi.nlm.nih.gov/35021063/(si apre in una nuova finestra)
Open access link to the manuscript = https://www.cell.com/cell/fulltext/S0092-8674(21)01481-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867421014811%3Fshowall%3Dtrue(si apre in una nuova finestra)
Citations of this article: this article has already been cited 90 times in less than one year.
Dissemination of this article to the general public: this article was featured in the Genome Web newsletter and in 526 social media posts.
Usage of the portal: this article is associated with a public portal where anyone can check the expression of genes in liver cells across species and in spatial datasets: https://www.livercellatlas.org/(si apre in una nuova finestra) This portal is used by 1000 different users every week since this article was published!
The spatial techniques used in this manuscript are central to WP2 and will form an important basis of the manuscript we are currently finalizing regarding the role of specific cell-cell interactions in liver regeneration. Indeed, we discovered a striking switch in tissue ligand expression in function of time and space during regeneration. We will therefore check if increasing or blocking this factors improves liver regeneration (WP4). This is still work in progress but should be finalized in the next 12 months.
We have followed the changes in gene expression profile of the different cells in function of time and space during liver regeneration. To do so we had to develop novel spatial technologies such as spatial CITE-seq: this technology allows to measure both RNA expression and protein expression spatially. These protocols were developed in close collaboration with the company 10X Genomics and have resulted in the publication of the first Human Liver Cell Atlas across species. This was a massive project involving two labs: the Guilliams lab (focusing on the healthy liver) and the Scott lab (focusing on the fatty-liver). Freya Svedberg developed essential spatial protocols for this study and is therefore co-author on this publication:
Pubmed link to this article = https://pubmed.ncbi.nlm.nih.gov/35021063/(si apre in una nuova finestra)
Open access link to the manuscript = https://www.cell.com/cell/fulltext/S0092-8674(21)01481-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867421014811%3Fshowall%3Dtrue(si apre in una nuova finestra)
Citations of this article: this article has already been cited 90 times in less than one year.
Dissemination of this article to the general public: this article was featured in the Genome Web newsletter and in 526 social media posts.
Usage of the portal: this article is associated with a public portal where anyone can check the expression of genes in liver cells across species and in spatial datasets: https://www.livercellatlas.org/(si apre in una nuova finestra) This portal is used by 1000 different users every week since this article was published!
The spatial techniques used in this manuscript are central to WP2 and will form an important basis of the manuscript we are currently finalizing regarding the role of specific cell-cell interactions in liver regeneration. Indeed, we discovered a striking switch in tissue ligand expression in function of time and space during regeneration. We will therefore check if increasing or blocking this factors improves liver regeneration (WP4). This is still work in progress but should be finalized in the next 12 months.
This project should have a major impact on the hepatology field. First, finding medical interventions that can accelerate liver regeneration will benefit cancer patients that are currently not eligible for a potentially curative resection because of an insufficient liver remnant. Second, providing therapies that can boost liver regeneration will augment the possibilities to perform living-donor liver transplantations, as surgeons will be able to use smaller liver grafts. Third, identifying the cell-cell circuits that form the blueprint of the liver tissue will be key to generate liver organoids. Finally, our automated spatial machine-learning pipelines will be applicable to the whole liver field and will help to study cell-cell interactions in other liver diseases.