Role of galectin-3 in liver progenitor cell proliferation and differentiation
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Liver progenitor cells (LPCs) respond to hepatic injury when hepatocyte division is impaired in chronic or severe injury. The LPCs are intimately surrounded by myofibroblasts, macrophages and laminin, thus constituting a potential progenitor cell niche. Laminin has been proposed to maintain LPCs in an undifferentiated state within the LPC niche. LPCs differentiate once they leave the laminin niche. However, mechanisms regulating this process have not been completely investigated. I hypothesized that cell membrane proteins which are implicated in intergin activation and mediation of cell adhesion to laminin such as galectin-3 and CD98 may be involved in this mechanism. Galectin-3 is a carbohydrate-binding protein which plays an important role in various cell functions, including cell growth, proliferation, adhesion, and differentiation. Galectin-3 has been reported to bind integrins and regulates β1 mediated adhesion to ECM. In addition, galectin-3 may also indirectly mediate β1 integrin activation by binding to and activating the heterodimeric transmembrane amino acid transporter CD98. However a role for galectin-3 in regulating LPC behavior has not been demonstrated. In this thesis, the mechanisms of galectin-3 mediating LPC proliferation and differentiation were investigated in an experimental model of LPC induction, the CDE diet, by using mutant mice lacking the gene encoding galectin-3. I have found galectin-3 is important for LPC induction and proliferation in vivo. In addition, galectin-3 is crucial for the LPC proliferation but is a negative regulator of LPC differentiation in vitro in a laminin dependent manner, suggesting that galectin-3 is required for LPC to maintain in an undifferentiated state on laminin. Moreover, the 2 extracellular binding activity of galectin-3 is important for LPC proliferation and adhesion to laminin. Furthermore, in the absence of galectin-3, LPCs down-regulate cyclin-D1 and the cyclin inhibitors p21 and p16 are elevated. Finally I suggest that integrin-β1 and CD98 are involved in regulating LPC proliferation. There is an increasing literature examining the role of LPC niche in regulating LPC behavior. My work suggests that galectin-3 is required for the expansion of LPCs in the injured adult liver. Galectin-3 enhances LPC adhesion to laminin. Galectin-3 is a crucial factor for LPCs to maintain in an undifferentiated state on laminin. My findings not only emphasize the requirement of LPCs to interact with their extracellular environment to expand but also propose that galectin-3 is a key signalling intermediary in the LPC niche, regulating homeostatic balance between proliferation and differentiation of LPCs, thus controlling regeneration.