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Functional Compensation Precedes Recovery of Tissue Mass Following Acute Liver Injury
Author(s) -
Walesky Chad,
Kolb Kellie,
Winston Carolyn,
Henderson Jake,
Kruft Benjamin,
Fleming Ira,
Ko Sungjin,
Monga Satdarshan P.,
Mueller Florian,
Apte Udayan,
Shalek Alex,
Goessling Wolfram
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03650
Subject(s) - wnt signaling pathway , liver injury , liver regeneration , gene knockdown , cancer research , biology , medicine , microbiology and biotechnology , regeneration (biology) , apoptosis , signal transduction , endocrinology , biochemistry
The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating 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 separate phases of liver recovery. Overall, our work describes a new mechanism by which the liver maintains essential physiological functions prior to cellular reconstitution and characterizes macrophage‐derived WNT signals required for this compensation. Support or Funding Information 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, the Pew‐Stewart Scholars Program for Cancer Research, a Sloan Fellowship in Chemistry, the NIH (1DP2GM1194192RM1HG0061931R01DA046277, and the Bill and Melinda Gates Foundation. U.A. is supported by R01DK098414.