Single Cell RNA‐sequencing (scRNA‐seq) Reveals Reprogramming and Functional Compensation Preceding Cellular Recovery in Multiple Models of Acute Liver Injury

Abstract

The liver is an essential organ critical for several homeostatic functions. Because of its vital role in detoxificaion, the liver is regularly exposed to toxic insults leading to injury, cell death, and a loss of functional mass. Consequently, the liver has evolved a unique capacity to regenerate in order to maintain function. While numerous studies have focused on the proliferative capacity of the liver to regenerate tissue mass after injury, the ability of the liver to maintain function after massive cell loss has not been explored in detail. Here, we deploy single cell RNA‐sequencing (scRNA‐seq) to define dynamic changes in the transcriptional profile of the liver following different forms of acute injury.Hepatocytes, the major parenchymal cell of the liver, are heterogeneous and arranged in a pattern consistent with their specific function, known as hepatic zonation. Select toxic insults will injure particular zones of the liver depending on zonation‐specific metabolism. One example is acetaminophen (APAP) toxicity, the most common cause of acute liver failure in the U.S. APAP affects a specific group of hepatocytes within an area known as the pericentral zone. In order to elucidate the immediate transcriptional responses of the entire liver after acute injury, we performed scRNA‐seq analysis in murine livers following APAP overdose compared to injury of the periportal zone (allyl alcohol) as well as physical injury that is not specific to a particular zone (partial liver resection). We discover that hepatocytes exhibit the ability to alter their transcriptional identity in order to maintain essential, zone‐dependent liver function, such as glucose metabolism, coagulation, and detoxification, prior to and during proliferative regeneration of liver mass. These findings are further validated and quantified by single‐molecule FISH. Further, our analysis reveals that zonal reprogramming is dependent on the Wnt pathway, which also regulates liver zonation and cellular regeneration. Therefore, we have identified a novel regenerative response that is focused on the preservation of function prior to the onset of cellular regeneration.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.