Functional compensation precedes recovery of tissue mass following acute liver injury

Chad Walesky (1) , Kellie Kolb (2, 3, 4, 5) , Carolyn Winston (1) , Jake Henderson (1) , Benjamin Kruft (1) , Ira Fleming (2, 3, 4, 5) , Sungjin Ko (6) , Satdarshan Monga (6) , Florian Mueller (7, 8) , Udayan Apte (9) , Alex Shalek (2, 3, 4, 10) , Wolfram Goessling (1, 3, 10, 11, 12, 13)

1 Brigham and Women’s Hospital [Boston, MA]
2 IMES - Institute of Medical Engineering & Science [Cambridge, MA]
3 BROAD INSTITUTE - Broad Institute of MIT and Harvard
4 Ragon Institute of MGH, MIT and Harvard
5 Koch Institute for Integrative Cancer Research at MIT [Cambridge, MA]
6 UPMC - University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis]
7 Imagerie et Modélisation - Imaging and Modeling
8 C3BI - Centre de Bioinformatique, Biostatistique et Biologie Intégrative
9 Department of Pharmacology, Toxicology, and Therapeutics [Kansas City, KS, USA]
10 Harvard-MIT Division of Health Sciences and Technology [Cambridge]
11 Dana-Farber Cancer Institute [Boston]
12 HSCI - Harvard Stem Cell Institute [Cambridge, USA]
13 Massachusetts General Hospital [Boston, MA, USA]

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/βcatenin signaling. Interestingly, transcriptional compensation is most prominent in nonproliferating 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.

Domaines: Santé publique et épidémiologie

Chad Walesky, Kellie Kolb, Carolyn Winston, Jake Henderson, Benjamin Kruft, et al.. Functional compensation precedes recovery of tissue mass following acute liver injury. Nature Communications, 2020, 11 (1), pp.5785. ⟨10.1038/s41467-020-19558-3⟩. ⟨pasteur-03648876⟩