The Role Of Notch Signaling Pathway In Liver Regeneration

Liver is one of the biggest organs of human beings. It plays a very import role in the maintenance of metabolism. Damage of liver tissue, such as chronic hepatitis, liver cirrhosis, may cause sever systemical disorder of body. However, liver is an organ with great potential to regenerate and liver regeneration could compensate part of the liver injury. But sometimes, chronic liver diseases like hepatitis result in abnormality of liver regeneration and finally lead to liver malfunction even death. Therefore, to realize the mechanism of liver regeneration is very important to guide the clinical practice for liver diseases.Liver regeneration is a compensative process following liver injury or partial hepatectomy. It totally bases on hepatocyte proliferation which depends on some cytokines such as HGF and IL-6. It has been well known that, these cytokines are mostly secreted by liver non parenchyma cells like sinusoidal endothelial cells (LSEC). We hypothesized that LSEC absolutely contribute to liver regeneration, because LSEC renew and proliferation is always accompanying with hepatic regeneration. In this project, we will focus on the change of LSEC function in order to illustrate their real effect on liver regeneration and some other mechanisms involved in it.Besides, researchers have confirmed bone marrow derived progenitor cells participate into liver regeneration through stimulating hepatocyte proliferation. Though no evidence was shown before, that bone marrow origin progenitor cells could directly differentiate into hepatocytes, a certain population of bone marrow derived cells named endothelial progenitor cells (EPC) was reported to differentiate into mature endothelial cells to rescue some tissue injury via recovery of damaged blood supply. Further more, during liver regeneration, a certain proportion of proliferating LSEC was bone marrow origin. These cells may directly differentiate into brand new LSEC or stimulate LSEC even hepatocyte proliferation through paracrine routine. In a word, both resident hepatic cells and bone marrow derived cells contribute to liver regeneration. To illustrate the mechanism of liver regeneration, both of them should be addressed.Notch signaling pathway is one of the most important transductive pathways for human body. It regulates cell proliferation, apoptosis, and cell fate decisions in a broad range of tissues during embryonic and postnatal development. Multiple members of Notch receptors (Notch1-4) and ligands (Dll1, 3, 4 and Jag1, 2), all of which are type I transmembrane proteins, have been identified in mammals. Recently, using a RBP-J conditional knock-out mouse model, we showed that blockade of the canonical Notch signaling in adult mice induced autonomous endothelial cell proliferation, suggesting that the Notch pathway is critical in the maintenance of vascular homeostasis.According to our previous findings, utilizing the well built rat partial hepatectomy and Notch/RBP-J conditional gene knock out mice model, we further illustrate how liver regeneration is regulated via the resident cell routine or the bone marrow derived cell routine. And especially figure out how these two routines were regulated by Notch signaling pathway. This is really helpful to guide the liver disease prevention and treatment.Our major findings were as follows: 1. Well built the Notch/RBP-J gene conditional knockout mice models;2. Disruption of Notch pathway led to loss of liver homeostasis. Liver hemorrhage, abnormal proliferation of hepatocytes and LSEC, and destroyed hepatic lobular structure were observed;3. Blocking Notch signaling interfered liver regeneration by inability of hepatocyte and SEC proliferation, liver hypertrophy and SEC dedifferentiation, and led to sinusoid obstructive syndrome and liver malfunction;4. In vitro experiment showed primarily cultured LSEC and hepatocytes were under Notch signaling regulation. Loss of Notch led to less VEGF, HGF and IL-6 secretion by LSEC;5. During liver regeneration, mobilization and recruitment of bone marrow derived progenitor cells were regulated by Notch pathway;6. Transplanted bone marrow cells without Notch signaling could not stimulate liver regeneration in total body irradiated rats;7. In vitro cultured EPC could not survive well with no Notch signaling. Loss of Notch resulted in defect of cell proliferation, adherence, colony formation, migration and vessel tube formation;8. EPC function was regulated by Notch signaling through CXCR4 pathway. Overexpression of CXCR4 could rescue the defect of vessel tube formation on EPC while Notch/RBP-J was knockout.In summary, liver regeneration depends on multiple cell interactions. Notch signaling pathway is essential for the maintenance of liver homeostasis and regulation of liver regeneration. Therefore, to realize the mechanism of liver regeneration is very important to guide the clinical practice for liver diseases.