Selected Publications

1. Nature

   Multimodal decoding of human liver regeneration

   K. P. Matchett, J. R. Wilson-Kanamori, J. R. Portman, C. A. Kapourani, F. Fercoq, S. May, E. Zajdel, M. Beltran, E. F. Sutherland, J. B. G. Mackey, M. Brice, G. C. Wilson, S. J. Wallace, L. Kitto, N. T. Younger, R. Dobie, D. J. Mole, G. C. Oniscu, S. J. Wigmore, P. Ramachandran, C. A. Vallejos, N. O. Carragher, M. M. Saeidinejad, A. Quaglia, R. Jalan, K. J. Simpson, T. J. Kendall, J. A. Rule, W. M. Lee, M. Hoare, C. J. Weston, J. C. Marioni, S. A. Teichmann, T. G. Bird, L. M. Carlin, and N. C. Henderson

   Nature May 2024

   Abs Bib URL

   The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3–5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut–liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

   @article{henderson2024liverregen,
     abbr = {Nature},
     url = {https://doi.org/10.1038/s41586-024-07376-2},
     title = {Multimodal decoding of human liver regeneration},
     author = {Matchett, K. P. and Wilson-Kanamori, J. R. and Portman, J. R. and Kapourani, C. A. and Fercoq, F. and May, S. and Zajdel, E. and Beltran, M. and Sutherland, E. F. and Mackey, J. B. G. and Brice, M. and Wilson, G. C. and Wallace, S. J. and Kitto, L. and Younger, N. T. and Dobie, R. and Mole, D. J. and Oniscu, G. C. and Wigmore, S. J. and Ramachandran, P. and Vallejos, C. A. and Carragher, N. O. and Saeidinejad, M. M. and Quaglia, A. and Jalan, R. and Simpson, K. J. and Kendall, T. J. and Rule, J. A. and Lee, W. M. and Hoare, M. and Weston, C. J. and Marioni, J. C. and Teichmann, S. A. and Bird, T. G. and Carlin, L. M. and Henderson, N. C.},
     journal = {Nature},
     year = {2024},
     month = may,
     publisher = {Nature Publishing Group},
     selected = {true}
   }

2. Spatial genomics: mapping human steatotic liver disease

   Kylie P. Matchett, Jasmin Paris, Sarah A. Teichmann, and Neil C. Henderson

   Nature Reviews Gastroenterology & Hepatology Apr 2024

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   Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease) is a leading cause of chronic liver disease worldwide. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH, formerly known as non-alcoholic steatohepatitis) with subsequent liver cirrhosis and hepatocellular carcinoma formation. The advent of current technologies such as single-cell and single-nuclei RNA sequencing have transformed our understanding of the liver in homeostasis and disease. The next frontier is contextualizing this single-cell information in its native spatial orientation. This understanding will markedly accelerate discovery science in hepatology, resulting in a further step-change in our knowledge of liver biology and pathobiology. In this Review, we discuss up-to-date knowledge of MASLD development and progression and how the burgeoning field of spatial genomics is driving exciting new developments in our understanding of human liver disease pathogenesis and therapeutic target identification.

   @article{henderson2024spatialreview,
     url = {https://www.nature.com/articles/s41575-024-00915-2},
     title = {Spatial genomics: mapping human steatotic liver disease},
     author = {Matchett, Kylie P. and Paris, Jasmin and Teichmann, Sarah A. and Henderson, Neil C.},
     journal = {Nature Reviews Gastroenterology & Hepatology},
     year = {2024},
     month = apr,
     publisher = {Nature Publishing Group},
     selected = {true}
   }

3. Nature

   Fibrosis: from mechanisms to medicines

   Neil C Henderson, Florian Rieder, and Thomas A Wynn

   Nature Nov 2020

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   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},
     month = nov,
     publisher = {Nature Publishing Group},
     selected = {true}
   }

4. 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 Nov 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},
     month = nov,
     publisher = {Elsevier},
     selected = {true}
   }

5. 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 Oct 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},
     month = oct,
     publisher = {Nature Publishing Group},
     selected = {true}
   }