Axin2-positive hepatocytes in adult mouse liver homeostasis and local injury repair
- Wnt signaling has been implicated in the regulation of many adult stem cell populations. Using the expression of the universal Wnt target gene, Axin2, our lab has identified a privileged population of Wnt responding hepatocytes adjacent to the central vein in the uninjured adult liver. Our lineage tracing studies show that Axin2+ hepatocytes self-renew and proliferate, contributing to normal liver tissue homeostasis. These Axin2+ hepatocyte stem cells are located adjacent to Wnt secreting endothelial cells of the central vein and express Tbx3, an embryonic hepatocyte progenitor marker. Additionally, these pericentral hepatocyte stem cells are diploid in nature, but give rise to mature polyploid hepatocytes that span the rest of the liver lobule. Thus, we conclude that pericentral Axin2+ hepatocytes, under the regulation of endothelial derived Wnt signaling, behave as hepatocyte stem cells in adult mouse liver homeostasis. Our finding that Wnt signaling regulates the proliferation of hepatocyte stem cells in the uninjured liver gave rise to the hypothesis that perhaps similar mechanisms may also regulate hepatocyte proliferation following injury. Carbon tetrachloride toxicity is a well-accepted experimental injury model that induces acute centrilobular necrosis in the liver, resulting in a localized liver injury. Carbon tetrachloride injury destroys pericentral hepatocyte stem cells, but interestingly, I found that de novo Wnt signaling is initiated during the injury repair process. Hepatocytes adjacent to the injury border express Axin2 approximately 2-3 days after injury. Lineage tracing and label dilution studies show that these injury-induced Wnt responding hepatocytes proliferate, actively contributing to the repair of the local damaged tissue. Interestingly, the hepatocyte progenitor marker Tbx3 is upregulated in hepatocytes that line the injury border during the repair process. Additionally, Wnt 2, 4, 5a, and 9b expression is upregulated following injury and is observed specifically in the damaged liver tissue. Functional studies show that blockade of Wnt secretion from endothelial cells in the injured liver results in delayed hepatocyte entry into the cell cycle following injury. Furthermore, deletion of beta-catenin, the major signal transducer of the Wnt signaling pathway, in Axin2+ hepatocytes following injury leads to delayed tissue repair and increased mortality. Together, these studies demonstrate the importance of Wnt signaling in regulating hepatocyte proliferation in both homeostasis and in response to local liver injury.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Stanford University, Program in Stem Cell Biology and Regenerative Medicine.
|Nusse, Roel, 1950-
|Nusse, Roel, 1950-
|Statement of responsibility
|Submitted to the Program in Stem Cell Biology and Regenerative Medicine.
|Thesis (Ph.D.)--Stanford University, 2017.
- © 2017 by Ludan Zhao
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...