Selected Publications

1. Nature

   Fibrosis: from mechanisms to medicines

   Neil C Henderson, Florian Rieder, and Thomas A Wynn

   Nature 2020

   Abs Bib URL

   Fibrosis can affect any organ and is responsible for up to 45% of all deaths in the industrialized world. It has long been thought to be relentlessly progressive and irreversible, but both preclinical models and clinical trials in various organ systems have shown that fibrosis is a highly dynamic process. This has clear implications for therapeutic interventions that are designed to capitalize on this inherent plasticity. However, despite substantial progress in our understanding of the pathobiology of fibrosis, a translational gap remains between the identification of putative antifibrotic targets and conversion of this knowledge into effective treatments in humans. Here we discuss the transformative experimental strategies that are being leveraged to dissect the key cellular and molecular mechanisms that regulate fibrosis, and the translational approaches that are enabling the emergence of precision medicine-based therapies for patients with fibrosis.

   @article{henderson2020fibrosis,
     abbr = {Nature},
     url = {https://doi.org/10.1038/s41586-020-2938-9},
     title = {Fibrosis: from mechanisms to medicines},
     author = {Henderson, Neil C and Rieder, Florian and Wynn, Thomas A},
     journal = {Nature},
     volume = {587},
     number = {7835},
     pages = {555--566},
     year = {2020},
     publisher = {Nature Publishing Group},
     selected = {true}
   }

2. Nature

   Resolving the fibrotic niche of human liver cirrhosis at single-cell level

   Prakash Ramachandran, Ross Dobie, John R Wilson-Kanamori, EF Dora, BEP Henderson, NT Luu, Jordan R Portman, Kylie P Matchett, Madara Brice, JA Marwick, RS Taylor, M Efremova, R Vento-Tormo, NO Carragher, TJ Kendall, JA Fallowfield, EM Harrison, DJ Mole, SJ Wigmore, PN Newsome, J Weston, JP Iredale, F Tacke, JW Pollard, Chris Ponting, John C Marioni, Sarah A Teichmann, and Neil C Henderson

   Nature 2019

   Abs Bib URL

   Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.

   @article{ramachandran2019resolving,
     abbr = {Nature},
     url = {https://doi.org/10.1038/s41586-019-1631-3},
     title = {Resolving the fibrotic niche of human liver cirrhosis at single-cell level},
     author = {Ramachandran, Prakash and Dobie, Ross and Wilson-Kanamori, John R and Dora, EF and Henderson, BEP and Luu, NT and Portman, Jordan R and Matchett, Kylie P and Brice, Madara and Marwick, JA and Taylor, RS and Efremova, M and Vento-Tormo, R and Carragher, NO and Kendall, TJ and Fallowfield, JA and Harrison, EM and Mole, DJ and Wigmore, SJ and Newsome, PN and Weston, J and Iredale, JP and Tacke, F and Pollard, JW and Ponting, Chris and Marioni, John C and Teichmann, Sarah A and Henderson, Neil C},
     journal = {Nature},
     volume = {575},
     number = {7783},
     pages = {512--518},
     year = {2019},
     publisher = {Nature Publishing Group},
     selected = {true}
   }

3. CellRep

   Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis

   Ross Dobie, John R Wilson-Kanamori, Beth EP Henderson, James R Smith, Kylie P Matchett, Jordan R Portman, Karolina Wallenborg, Simone Picelli, Anna Zagorska, Swetha V Pendem, TE Hudson, MM Wu, GR Budas, DG Breckenridge, EM Harrison, DJ Mole, SJ Wigmore, Prakash Ramachandran, Chris P Ponting, Sarah A Teichmann, John C Marioni, and Neil C Henderson

   Cell reports 2019

   Abs Bib

   Iterative liver injury results in progressive fibrosis disrupting hepatic architecture, regeneration potential, and liver function. Hepatic stellate cells (HSCs) are a major source of pathological matrix during fibrosis and are thought to be a functionally homogeneous population. Here, we use single-cell RNA sequencing to deconvolve the hepatic mesenchyme in healthy and fibrotic mouse liver, revealing spatial zonation of HSCs across the hepatic lobule. Furthermore, we show that HSCs partition into topographically diametric lobule regions, designated portal vein-associated HSCs (PaHSCs) and central vein-associated HSCs (CaHSCs). Importantly we uncover functional zonation, identifying CaHSCs as the dominant pathogenic collagen-producing cells in a mouse model of centrilobular fibrosis. Finally, we identify LPAR1 as a therapeutic target on collagen-producing CaHSCs, demonstrating that blockade of LPAR1 inhibits liver fibrosis in a rodent NASH model. Taken together, our work illustrates the power of single-cell transcriptomics to resolve the key collagen-producing cells driving liver fibrosis with high precision.

   @article{dobie2019single,
     abbr = {CellRep},
     title = {Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis},
     author = {Dobie, Ross and Wilson-Kanamori, John R and Henderson, Beth EP and Smith, James R and Matchett, Kylie P and Portman, Jordan R and Wallenborg, Karolina and Picelli, Simone and Zagorska, Anna and Pendem, Swetha V and Hudson, TE and Wu, MM and Budas, GR and Breckenridge, DG and Harrison, EM and Mole, DJ and Wigmore, SJ and Ramachandran, Prakash and Ponting, Chris P and Teichmann, Sarah A and Marioni, John C and Henderson, Neil C},
     journal = {Cell reports},
     volume = {29},
     number = {7},
     pages = {1832--1847},
     year = {2019},
     publisher = {Elsevier},
     selected = {true}
   }