Biomedical Engineering Reference
In-Depth Information
9.5.1 ß Cell Replication
Regarding the expansion of b cells, the first source that comes to mind is the b cell
itself. It would be an ideal approach to expand b cells in vitro and transplant them
back to treat diabetes. Proliferation of b cells is well known to occur in the adult
mouse pancreas under normal conditions as well as during the regeneration of
pancreas [
25
,
32
]. Beta cell replication was also shown to be the primary mech-
anism involved in the early postnatal expansion of b cell mass in human indi-
viduals [
109
]. However, the replication of b cells in vitro is difficult to analyze as
they gradually dedifferentiate and lose insulin expression [
110
,
111
]. This makes it
difficult to determine whether the replicating cells in the culture are b cells that
have now lost their phenotype or they belong to some other cell type in the
pancreas. To confirm the dedifferentiation and replication of b cells in vitro,
Weinberg et al. [
112
] cultured b cells isolated from transgenic mice that perma-
nently expressed YFP (yellow fluorescent protein) in b cells only. Indeed, it was
found that these labeled b cells gradually lost insulin expression while they
remained positive for YFP. However, under the culture conditions used the rep-
lication of b cells was rare even after they lose their phenotype. In another study by
Parnaud et al. [
113
], proliferation of b cells isolated from adult humans and rats
was compared. While rat b cells were able to proliferate under the culture con-
ditions used, human b cells did not show this capacity. However, a lineage tracing
approach was not used leaving a doubt that some dedifferentiated b cells might
have proliferated in the culture. Russ et al. [
114
] used a lineage tracing approach to
efficiently study the in vitro proliferation of b cells isolated from adult human
islets. They used lentivirus vectors to label insulin-positive b cells with GFP
(green fluorescent protein) and traced these cells in the culture. As found in other
studies, these cells lost insulin expression but kept on proliferating in the culture
up to 16 population doublings. It was also found that the presence of pancreatic
non-b cells or a medium conditioned by pancreatic non-b cells was required for
active proliferation of these GFP-labeled cells. However, consistent with the
previous study by Weinberg et al. [
112
], mouse b cells showed much lower
replication under similar culture conditions. Collectively, these studies show that b
cells dedifferentiate when cultured in vitro and the proliferation of dedifferentiated
b cells depends on the species and culture conditions used. Furthermore, the
capacity of dedifferentiated b cells to expand in vitro is of therapeutic importance
as well. Such dedifferentiated b cells are thought to retain some of the b cell
characteristics that can make it easier to redifferentiate them into functional b cells
for therapeutic use. Future studies will focus on the possible ways to redifferentiate
these cells and to determine the functional maturity of b cells generated in this
way.
