How do tissue mechanics affect cell state?
Supervisor: Dr Luke Boulter
In many tissues, stem cells reside in special microenvironments that maintain them in a naïve state. In the liver, the existence of a tissue stem cell is controversial, rather differentiated cells seem to be able to exit their normal cell state and become dedifferentiated progenitor cells (Raven et al 2017). Our group has shown that these “progenitor cells” can regenerate new ducts in the liver (Boulter et al 2013, Wilson et al 2020) but the question remains, how do they know where to regenerate a new duct?
Using sophisticated 3D ductular cultures and in vivo models of ductular regeneration, we will address this question and define whether changes in tissue forces are enough to trigger regeneration.
Raven A, Lu WY … Boulter L, Forbes SJ. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature. 2017 Jul 20;547(7663):350-354. doi: 10.1038/nature23015. Epub 2017 Jul 12. PMID: 28700576; PMCID: PMC5522613.
Boulter L, Govaere O, … Forbes SJ. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012 Mar 4;18(4):572-9. doi: 10.1038/nm.2667. PMID: 22388089; PMCID: PMC3364717.
Wilson DH, Jarman EJ … Boulter L. Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors. Nat Commun. 2020 Jan 23;11(1):445. doi: 10.1038/s41467-020-14283-3. PMID: 31974352; PMCID: PMC6978415.