Biomedical Engineering Reference
In-Depth Information
factors (Pdx1, Ngn3, and MafA) in exocrine cells. A combination of these three
factors successfully converted acinar cells into b cells that were indistinguishable
from normal b cells. These newly generated cells expressed b cell-specific markers
and were able to reduce hyperglycemia in streptozotocin-induced diabetic mice;
however, a complete normoglycemia was not achieved. One possible reason could
be the insufficient number of b cells generated in this way. Second, the new b cells
failed to organize into islet structures that might have limited their effectiveness.
Regardless of this, conversion of acinar cells into insulin-producing cells in vivo is
an important advance that has the potential to treat diabetes.
Alpha Cells
Direct conversion of glucagon producing a cells into b cells can take place under
certain conditions, e.g., during injury-induced b cell regeneration in rodent models
[
33
,
171
]. In humans, a small number of glucagon cells co-positive for insulin
were found in the pancreata of acute pancreatitis patients, however, their con-
version into mature b cells was not confirmed [
171
]. Conversion of a into b cells
is, therefore, not a frequent or easily induced process. Loss-of-function studies in
mice have identified Pax4 and Arx as two important transcription factors that play
a role in the specification of b and a cells respectively [
172
,
173
]. Additionally, it
was found that Pax4 and Arx have opposing roles: a misexpression of Arx in b
cells can convert them into a cells and that of Pax4 in a cells converts them into b
cells [
174
,
175
]. In this study by Collombat et al. [
175
], a Cre/loxP system was
used to overexpress Pax4 in glucagon cells that led to their transdifferentiation into
b cells. The resulting decrease in the level of glucagon was compensated by the
generation of new glucagon cells from the ductal progenitors. This continuous
cycle of a cell generation and conversion into b cells led to the formation of mega-
islets. In spite of these oversized islets with increased insulin content, older mice
developed hyperglycemia that might be due to the acquired insulin resistance.
However, these newly generated b cells did restore normoglycemia in younger
(less than 4 week old) mice that were treated with streptozotocin to kill b cells.
Although, currently far from clinical application, such transdifferentiation of a to b
cells, holds great potential for the treatment of diabetes. Future studies will be
focused on finding alternative ways to easily induce this process in a clinical
setting, e.g., treatment with some biomolecules instead of genetic manipulation.
9.6 Xenotransplantation: Pig Islets as an Alternative
Source of b Cells
Xenotransplantation of pig islets, if made possible, can circumvent the shortage of
available donor pancreas/islets. As compared to whole organs, transplantation of
pig
islets
into
non-human
primates
has
shown
more
promising
results
[
176
].
