1. Functional compensation precedes recovery of tissue mass following acute liver injury
- Author
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Ira Fleming, Carolyn Winston, Benjamin Kruft, Alex K. Shalek, Wolfram Goessling, Satdarshan P.S. Monga, Florian Mueller, Sungjin Ko, Udayan Apte, Chad Walesky, Kellie E. Kolb, Jake Henderson, Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), Institute of Medical Engineering & Science [Cambridge, MA] (IMES), Massachusetts Institute of Technology (MIT), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Ragon Institute of MGH, MIT and Harvard, Koch Institute for Integrative Cancer Research at MIT [Cambridge, MA], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Department of Pharmacology, Toxicology, and Therapeutics [Kansas City, KS, USA], University of Kansas Medical Center [Kansas City, KS, USA], Harvard-MIT Division of Health Sciences and Technology [Cambridge], Dana-Farber Cancer Institute [Boston], Harvard Stem Cell Institute [Cambridge, USA] (HSCI), Harvard University, Massachusetts General Hospital [Boston, MA, USA], and C..W. is supported by F32DK111151, the Cholangiocarcinoma Foundation Research Fellowship, and the American Liver Foundation Charles Trey, MD Memorial Post-doctoral Research Fellowship. W.G. is supported by R01DK090311, R01DK105198, R24OD017870, and the Claudia Adams Barr Program for Excellence in Cancer Research. W.G. is a Pew Scholar in Biomedical Sciences. A.K.S. was supported, in part, by the Searle Scholars Program, the Beckman Young Investigator Program, a Sloan Fellowship in Chemistry, the NIH (1DP2GM1194192 & RM1HG0061931), and the MIT Stem Cell Initiative through Fondation MIT. U.A. is supported by R01DK098414. S.P.M is supported by NIH/NIDDK P30DK120531, Pittsburgh Liver Research Centre Grant, and NIH/NIDDK (DK62277, DK100287, and CA204586)
- Subjects
0301 basic medicine ,MESH: beta Catenin ,General Physics and Astronomy ,MESH: Cell Cycle ,MESH: Mice, Knockout ,Biochemistry ,Transcriptome ,MESH: Hepatocytes ,Mice ,0302 clinical medicine ,Protein biosynthesis ,MESH: Animals ,lcsh:Science ,Wnt Signaling Pathway ,beta Catenin ,Mice, Knockout ,Multidisciplinary ,Fluorescence in situ hybridization ,Cell Cycle ,MESH: Wnt Signaling Pathway ,Wnt signaling pathway ,Cell cycle ,MESH: Hepatectomy ,Liver regeneration ,Cell biology ,MESH: Wnt Proteins ,Liver ,030211 gastroenterology & hepatology ,MESH: Liver Regeneration ,Reprogramming ,Biotechnology ,Science ,MESH: Acetaminophen ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,MESH: Gene Expression Profiling ,MESH: Mice, Inbred C57BL ,MESH: Cell Proliferation ,Detoxification ,Genetics ,Animals ,Hepatectomy ,Transcriptomics ,MESH: Mice ,Molecular Biology ,Acetaminophen ,Cell Proliferation ,Mechanism (biology) ,Gene Expression Profiling ,Macrophages ,MESH: Macrophages ,General Chemistry ,Regenerative process ,Liver Regeneration ,Gene expression profiling ,Mice, Inbred C57BL ,Wnt Proteins ,Disease Models, Animal ,030104 developmental biology ,Hepatocytes ,lcsh:Q ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Liver function ,MESH: Disease Models, Animal ,MESH: Liver - 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., The liver possesses the ability to regenerate following sudden injury. Here, the authors use single-cell RNA-sequencing and in situ transcriptional analyses to identify a new phase of liver regeneration in mice aimed at maintaining essential functions throughout the regenerative process.
- Published
- 2020