Functional compensation precedes recovery of tissue mass following acute liver injury

Chad M. Walesky, Kellie E. Kolb, Carolyn L. Winston, Jake Henderson, Benjamin Kruft, Ira Fleming, Sungjin Ko, Satdarshan P. Monga, Florian Mueller, Udayan Apte, Alex K. Shalek () and Wolfram Goessling ()
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Chad M. Walesky: Brigham and Women’s Hospital, Harvard Medical School
Kellie E. Kolb: Institute of Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Carolyn L. Winston: Brigham and Women’s Hospital, Harvard Medical School
Jake Henderson: Brigham and Women’s Hospital, Harvard Medical School
Benjamin Kruft: Brigham and Women’s Hospital, Harvard Medical School
Ira Fleming: Institute of Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Sungjin Ko: University of Pittsburgh, School of Medicine; and Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center
Satdarshan P. Monga: University of Pittsburgh, School of Medicine; and Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center
Florian Mueller: Imaging and Modeling Unit, Institut Pasteur, UMR 3691CNRS, C3BI USR 3756 IP CNRS
Udayan Apte: Toxicology, and Therapeutics, University of Kansas Medical Center
Alex K. Shalek: Institute of Medical Engineering & Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Wolfram Goessling: Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating cellular proliferation during liver repair have been identified, the mechanisms by which the injured liver maintains vital functions prior to tissue recovery are unknown. Here, we identify a new phase of functional compensation following acute liver injury that occurs prior to cellular proliferation. By coupling single-cell RNA-seq with in situ transcriptional analyses in two independent murine liver injury models, we discover adaptive reprogramming to ensure expression of both injury response and core liver function genes dependent on macrophage-derived WNT/β-catenin signaling. Interestingly, transcriptional compensation is most prominent in non-proliferating cells, clearly delineating two temporally distinct phases of liver recovery. Overall, our work describes a mechanism by which the liver maintains essential physiological functions prior to cellular reconstitution and characterizes macrophage-derived WNT signals required for this compensation.

Date: 2020
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DOI: 10.1038/s41467-020-19558-3

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