Liver Regeneration: Underlying Fundamentals of Stem Cell Application in Liver Disease Treatment

Studies of liver regeneration capacity were first demonstrated by partial hepatectomy (PH) in rats and mice (Zhao et al. 2009). After 10 days of PH, one-third of rat/mouse liver tissue that remained after the PH procedure could regenerate and fill the empty liver mass. The PH model demonstrated the mechanism of liver generation (Alison et al. 2009; Kang et al. 2012). It is possible that many cells are involved in liver regeneration after PH. However, scientists suggest two main mechanisms related directly to liver regeneration and restoration of liver mass. Firstly, although hepatocytes are differentiated cells, during liver injury they can activate themselves; the mechanism is called self-proliferation (Zhao et al. 2009). Many studies have shown that liver stem cells can be elevated in liver damage. These stem cells can differentiate into liver cells and biliary epithelial cells and are called bipotent progenitor cells or liver progenitor cells (Thorgeirsson 1996; Zhao et al. 2009). In rodents, these progenitor cells are called “oval cells.” The repopulation of liver from liver progenitor cells is a process known as trans-differentiation (Kang et al. 2012; Zhao et al. 2009). Secondly, in addition to cells/stem cells, molecular signals play an important role in liver generation (Kang et al. 2012). Experiments in rats demonstrated the important role of circulating growth factors, such as hepatocyte growth factor (HGF) and transforming growth factor alpha (TGF-a), which are involved in hepatocyte proliferation (Kang et al. 2012). Together with circulating growth factors, cell-cell interaction and cell- matrix reorganization also play vital roles in liver regeneration (Kang et al. 2012). For instance, urokinase-type plasminogen activator (uPA) is released soon after PH and induces the reorganization of extracellular matrix via activation of metallopro- teinases (MMP) and HGF (Kang et al. 2012; Kim et al. 2000). Overall, the liver regeneration process is dependent on mechanisms that relate to liver cells/progenitor cells and molecular signals (Alison et al. 2009; Kang et al. 2012).

Along with the understanding of liver regeneration, a greater understanding of stem cell biology could advance the application of stem cells for liver cirrhosis treatment. Stem cells are defined as cells with self-renewal capability and potential to differentiate into specific cell types. Because of these features, stem cells can provide considerably beneficial for use in liver cirrhosis therapy. First, self-stem cells can generate numerous cells. In treating liver disease, a major problem is limited cell quantity; use of stem cells could overcome this obstacle. Second, many studies have revealed that stem cells can differentiate into hepatocyte like cells (Anna et al. 2010; Forbes and Newsome 2012) (Bagher et al. 2012; Zhang et al. 2012; Zhao et al. 2009). In vivo studies have also demonstrated the great potential of stem cells to ameliorate liver disease. Stem cells not only can retain their ability to renew and rejuvenate new cells in response to injury, but they also play a key role in many important physiological processes (Anna et al. 2010). In the case of liver cirrhosis, the use of targeted drugs can help reduce injury but cell therapy can overturn damage by supplying new functional cells. Compared to the mechanism of liver regeneration in PH, stem cell therapy can cure liver disease by similar means. The consideration of therapeutic mechanism of MSCs in liver cirrhosis, the kinds of stem cells that should be used, and strategies for liver cirrhosis treatment continue to be debated and controversial.

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