Liver Zonation

• Glucagon regulates liver zonation through the Wnt/β-catenin pathway
  While Wnt signaling regulates a portion of the liver zonation genes, the regulation of a majority of these genes remains unknown. Cheng et al. show that glucagon is an important regulator of metabolic zonation in the liver. RNAscope ISH revealed the effects of glucagon on the expression of periportal and perivenous genes in specific layers of liver zonation.

Liver Fibrosis

• Assessment of fibrosis and RXFP1 expression in human liver
  Despite the clinical burden and advances in understanding the pathogenesis of liver fibrosis, there are still no approved antifibrotic therapies. McBride et al. sought to identify a small molecule agonist for the relaxin GPCR RXFP1 for liver fibrosis treatment. They used RNAscope ISH to assess RXFP1 expression and distribution in human liver biopsies from 2 types of liver fibrosis, AIH and NASH.

Gene Therapy in Liver

• Delivery of hEPO mRNA to hepatocytes by lipid nanoparticles
  mRNA therapy provides transient production of therapeutic proteins without the need for nuclear delivery or risk of insertional mutagenesis. DeRosa et al. used lipid nanoparticles to deliver hEPO and hFIX mRNA, showing that exogenous mRNA-derived protein maintains normal activity, confirmed delivery of the mRNA therapy to hepatocytes and that the mRNA therapy degraded over time.

Steatosis

• Senescent cells promote hepatic fat accumulation and steatosis
  Non-alcoholic fatty liver disease (NAFLD) is characterized by excess hepatic fat (steatosis) and its incidence increases with age. Ogrodnik et al. show that accumulation of senescent cells promote hepatic fat accumulation and steatosis, and that targeting senescent cells could be a therapeutic to reduce steatosis in NAFLD. RNAscope ISH demonstrated that a high fat diet increased expression of p16 (a senescence marker) but treatment with an apoptosis-inducer reduced expression of p16.

Regeneration

• Hepatocyte homeostasis and renewal in the liver
  The cellular source of new hepatocytes in the uninjured adult liver remains an unanswered question. Wang et al. identify a cell population in the liver (Wnt-responsive Axin2+ diploid cells) that serves to renew hepatocytes, characterize its niche and identify the signals that regulate its activity. RNAscope ISH was used to show in the adult mouse liver where the Wnt-target gene Axin2 is expressed and identify the precise cells producing Wnts.

Cellular Source of Secreted Proteins

• Expression of the angiokine Bmp2 in liver sinusoidal endothelial cells
  Organ-specific endothelial cells control their tissue microenvironment by producing angiocrine growth factors known as angiokines to stimulate blood vessel growth. Bmp2 has been identified as an organ-specific angiokine derived from liver sinusoidal endothelial cells (LSECs). Koch et al. used RNAscope to show Bmp2 expression in LSECS and confirm deletion of Bmp2 specifically in LSECs to understand Bmp2 signaling in the liver.