Cellular Plasticity during Regeneration
The ability to regenerate complex organs requires generation of multiple cell-types, which is achieved by three means:
- Proliferation of resident stem cells, such as in skin, intestine or blood.
- Self-renewal of spared functional cells, such as in heart regeneration or upon mild injury of pancreatic β-cell or liver.
- Transdifferentiation of a functional cell into another, such as upon a severe injury to bone cells, pancreatic β-cells or liver hepatocytes.
Among the three means of cellular recovery, the third method, transdifferentiation, is peculiar as it is not the default mode of regeneration. For instance, mild injury to pancreatic β-cell or liver hepatocytes is recovered by self-renewal, while a total loss of these cells is compensated by transdifferentiation. Thus, transdifferentiation is facultative: occurring only when the primary source of regeneration is missing. Moreover, transdifferentiation is not perfect. For example, the transdifferentiation of pancreatic δ-cells to β-cells in zebrafish leads to the formation of hybrid cells (Fig. 2) that contain characteristics of δ- and β-cells.
The goal of our current research is to understand the regulators of such regenerative plasticity.
In line with this, we have started work on liver regeneration in zebrafish to accomplish these goals, as the liver provides an evolutionary conserved model to study the cellular mode of regeneration. The zebrafish liver is highly similar to the human liver, conserving both cellular composition and functionality. It consists of two major cell types: the hepatocytes and biliary epithelial cells (BECs or cholangiocytes or ductal cells). Hepatocytes perform most of the liver functions, while BECs transport bile acid produced by hepatocytes to the gallbladder.
Liver regeneration in zebrafish and mammals is facultative. Upon mild injury, for example loss of less than 75% of the liver by partial hepatectomy, the remaining hepatocytes proliferate to regenerate the remaining tissue. However, upon severe injury or when the cell-cycle in hepatocytes is blocked, the biliary epithelial cells (BECs) transdifferentiate to generate new hepatocytes. In our lab we are investigating the regulators of BECs-to-hepatocyte conversion.