2017 research grant award spotlight: katzmann, “apical and basolateral exosome signaling in normal and psc cholangiocytes”

Each year, PSC Partners asks research grant awardees to share a lay summary as part of our grant process.  In order to make this information more digestible and shine a light on each individual study, we will share a summary each week (in alphabetical order of the Principal Investigator’s last names).  We welcome your comments or thoughts for the researchers at the bottom of each of these blog posts, and are excited to share this new PSC-related research with you!

Title: Apical and Basolateral Exosome Signaling in Normal and PSC Cholangiocytes

Principal Investigator:
David J. Katzmann, PhD, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN

Brief Lay Summary:
Changes in cholangiocyte cell-to-cell communication likely contribute to development of PSC. Exosomes, a type of extracellular vesicle, represent a newly appreciated mode of intracellular communication. Preliminary studies indicate that: i) PSC cell lines and senescent cholangiocyte models of PSC secrete more exosomes than normal cholangioctes, and ii) exosomes from PSC cell lines and senescent cholangiocyte models of PSC activate cholangiocytes and macrophages more potently than exosomes from normal cholangiocytes. As polarized epithelia, cholangiocytes would be expected to release distinct exosomes from their apical and basolateral domains to mediate communication to targets via the bile duct (apical targets: cholagiocytes or intestinal epithelial cells) or targets within the peribiliary milieu (basolateral targets: macrophages, hepatic stellate cells). Preliminary studies supports this model as: i) normal polarized cholangiocytes release exosomes both apically and basolaterally, ii) apical and basolateral exosomes differ in the number, protein contents, and RNA contents, and iii) apical and basolateral exosomes exhibit distinct signaling activities. Our initial observations have led to the hypothesis that cholangiocytes release domain-specific (i.e., apical versus basolateral) subpopulations of exosomes containing cargo that differentially influence the phenotype of target cells in normal and diseased states, thereby contributing to liver homeostasis or development of PSC. This hypothesis will be tested by two aims: 1) define the protein contents of apical and basolateral exosomes released from normal and PSC cholangiocyte models and address the contributions of these protein constituents to exosome-induced signaling in apical and basolateral target cells; 2) define the RNA contents of normal and PSC cholangiocyte apical and basolateral exosomes and investigate the contributions of miRNA in polarized exosome signaling in normal and diseased states.