Pancreatic Reprogramming - Regenerative Medicine and Cell Therapy - page 155

mesoderm is known to signal the ventral endoderm to instruct early liver
specification in vertebrates [ 33 - 35 ], and it has been demonstrated that both organs
stem out from a common pool of endodermal progenitors in the early foregut
[ 35 - 43 ]. A potential mechanism behind this specification was proposed FGF-
dependent [ 37 ], and the proximity to the FGF-producing cardiac mesoderm would
be the main factor dictating pancreatic (distal) or hepatic (proximal) specification
from this progenitor pool.
Similarities between liver and pancreas are evidenced not only by their shared
ancestry but also by the makeup of key cellular hardware, such as that needed for
glucose secretion and sensing. In fact, it is known that virtually 100 % of the
mammalian reservoir of the glucose-sensing enzyme glucokinase, which is
responsible for the systemic maintenance of glucose homeostasis by regulating the
balance between insulin release and glycogen storage, is restricted to hepatocytes
and beta cells [ 44 - 46 ]. Because of this close relationship between the two organs,
it does not come as a surprise that certain experimental conditions result in the
interconversion of liver and pancreas. Pancreas is typically converted to liver in
rats subjected to a copper-depleted diet [ 47 - 49 ] and upon treatment with dexa-
methasone [ 50 ]. The opposite has also been observed following exposure to di-
ethylnitrosamine [ 51 ] or as a consequence of tumoral processes [ 52 ].
8.2 Directed Reprogramming of Liver to Pancreas
Because of the above evidence, the liver stood out fairly soon as one strong
candidate for pancreatic cell reprogramming. As expected, the quest for specific
factors that could act as post-developmental switches between liver and pancreas
started with the study of Pdx1. The pancreatic and duodenal homeobox 1 (Pdx1)
gene is preferentially expressed in the beta cells of the islet, where it exerts a tight
control over insulin secretion by binding to the insulin promoter [ 53 ]. Because of
this role, Pdx1 is the main responsible for the maintenance of the beta cell identity.
Experiments in which Pdx1 is conditionally knocked out in adulthood [ 54 , 55 ]
revealed that heterozygous mice display an age-dependent decrease in glucose
tolerance, impaired glucose-stimulated insulin release, and higher rates of beta cell
apoptosis [ 56 ]. The full beta cell-specific knockout resulted in total loss of the beta
cell phenotype and mature onset of diabetes [ 54 ]. The defective glucose-mediated
insulin response in P. obesus, a type 2 diabetes mouse model, was also linked to
Pdx1 deficiency [ 57 , 58 ].
The influence of Pdx1 in pancreatic development has also been extensively
established. Its expression around e8.5 (10—somite stage) in the murine foregut is
the true hallmark of pancreatic versus liver specification. Embryos homozygous for
Pdx1 inactivating mutations are born without pancreas [ 59 ], a phenotype that has
also been described in humans with a single nucleotide mutation of the gene [ 60 ].
Coincident with a down-regulation of the pro-intestinal factor sonic hedgehog
(Shh), Pdx1 expression will delineate the regions that will later become the dorsal