An alternative to the use of undifferentiated cells is that of reprogramming adult cells from nonpancreatic sources. Of these, the most promising is the liver, whose embryonic development is deeply intertwined with that of the pancreas. Several teams have now proven that the ectopic expression of master pancreatic regulators such as Pdx1 or MafA, among others, can induce the expression of pancreatic markers in liver-derived cells, both in vitro and in vivo. Here we review the status and clinical prospects of this approach.
Liver transdifferentiation • Pdx1 • VP16 • Reprogramming • Hepatocytes
Expression of Pdx1 in the foregut (e8) is one of the earlier molecular events that mark the specification of the pancreas as a separate organ (see the chapter “Pancreatic Development”). The role of Pdx1 as a “master regulator” of pancreatic development has led many investigators to test whether its ectopic expression would induce pancreatic differentiation by itself. This strategy has yielded somewhat modest results in most cellular substrates examined which suggests that Pdx1 expression is necessary, but not sufficient, to initiate pancreatic development. The conclusion from the observation that the initial evagination of the pancreatic epithelium occurs even in the absence of Pdx1.A possible exception to this rule, however, is observed when the target tissue is liver.In fact, there is a wealth of studies indicating that the liver and pancreas are especially susceptible to interconversion. Many invertebrates have a single organ that comprises both hepatic and pancreatic functions, which suggests that the separation of these two organs is a relatively late evolutionary event. In vertebrates, fibroblast growth factor (FGF) signals from the cardiac mesoderm have been shown to play an essential role for the ventral endoderm to differentiate into early hepatic cells and it has been demonstrated that both organs originate from common endodermal progenitors in the early foregut.According to the model described by Deutsch et al., 662 cardiac FGF will have inductive and blocking effects on liver and pancreas specification, respectively.
In general, hepatocytes and beta cells share not only many developmental features but also similar molecular machinery for glucose sensing and secretion. Many studies confirm that interconversion of liver and pancreas occurs under a variety of experimental conditions, including copper depletion in rats treatment with dexamethasone or diethylnitrosamine and certain tumoral processes.
FGF signalling from the cardiac mesoderm will induce liver specification proximally ( dotted region ), but will have a blocking effect on the distal portion of the ventral foregut, which will become pancreas ( stripes ) (Adapted from Deutsch et al.
Tags: FGF signalling from the cardiac mesoderm, Hepatocytes, hepatocytes and beta cells, Liver transdifferentiation, liver-derived cells, nonpancreatic sources, Pdx1, reprogramming adult cells, undifferentiated cells, VP16