Graphic depicting the research described in the article and caption below.

a Time course depicting analysis time points during liver injury recovery following APAP overdose or PH. b Murine liver sections (5 μm, n = 3) show necrotic TUNEL-positive (brown, top) and proliferative PCNA-positive (brown, bottom) cells. Scale bar is 100 μm. c Bar graphs quantifying total TUNEL- and PCNA-positive area. Error bars are s.e.m., P < 0.05 (*), < 0.01 (**), and < 0.0001 (****) calculated using unpaired t test with Welch’s correction (two-tailed). d t-SNE plot of all high-quality hepatocytes (Methods) in the scRNA-Seq dataset. Cells are colored by injury mode and time point. SNN clusters outlined in black. e Heatmap of marker genes for all clusters outlined in (d). f, g Pericentral Hepatocyte Signature Score (PCH Signature Score) (left). Violin plot of normalized expression of Cyp2e1 (middle) and Glul (right); percent positive calculated as percentage of total cells in each condition above average normalized genes expression (dashed red line). Untreated (UT) and each post-treatment are plotted for APAP (f) and PH (g). Source data provided as a Source Data file.

Image via Nature Communications.

Shalek paper published in Nature Communications

by Danielle Doughty | Department of Chemistry |
Categories: Faculty, Research

The paper, “Functional compensation precedes recovery of tissue mass following acute liver injury", was published on November 19, 2020.

A paper authored by Chad M. Walesky, Kellie E. Kolb, Carolyn L. Winston, Jake Henderson, Benjamin Kruft, Ira Fleming, Sungjin Ko, Satdarshan P. Monga, Florian Mueller, Udayan Apte and Alex K. Shalek was published in Nature Communications on November 19, 2020.

Functional compensation precedesrecovery of tissue mass following acuteliver 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 and Alex K. Shalek
Nature Communications 11, 5785 (2020)
DOI: https://doi.org/10.1038/s41467-020-19558-3

The liver plays a central role in metabolism, protein synthesis and detoxification.It possesses unique regenerative capacity upon injury. While many factorsregulating cellular proliferation during liver repair have been identified, themechanisms by which the injured liver maintains vital functions prior to tissuerecovery are unknown. Here, we identify a new phase of functional compensationfollowing acute liver injury that occurs prior to cellular proliferation. By couplingsingle-cell RNA-seq with in situ transcriptional analyses in two independentmurine liver injury models, we discover adaptive reprogramming to ensureexpression of both injury response and core liver function genes dependent onmacrophage-derived WNT/β-catenin signaling. Interestingly, transcriptionalcompensation is most prominent in non-proliferating cells, clearly delineatingtwo temporally distinct phases of liver recovery. Overall, our work describes amechanism by which the liver maintains essential physiological functions prior tocellular reconstitution and characterizes macrophage-derived WNT signalsrequired for this compensation.

The Shalek Lab creates and implements new approaches to elucidate cellular and molecular features that inform tissue-level function and dysfunction across the spectrum of human health and disease.