With autoimmune type I diabetes requiring potentially injurious insulin
injections several times a day and type II diabetes showing a growing role for
insulin-producing pancreatic islets in disease progression, researchers around
the world are searching for better ways to cope.
New animal research at
the Technion-Israel Institute of Technology in Haifa and Ben-Gurion University
of the Negev in Beersheba offer the hope that one day, transplants of tissue
from the pancreas could lead to better glucose control for
Prof. Shulamit Levenberg of the Technion, who has spent many
years trying to create replacement human organs by building them up on a
“scaffold,” has created tissue from the insulin-producing islets of Langerhans
in the pancreas surrounded by a three-dimensional network of blood
The tissue she and her team created has significant advantages
over traditional transplant material that has been harvested from healthy
The insulin-producing cells survive longer in the
engineered tissue, and produce more insulin and other essential hormones,
Levenberg and colleagues wrote in the latest issue of the US medical journal
PLOS One. When they transplanted the tissue into diabetic mice, the cells began
functioning well enough to lower blood sugar levels in the
Transplantation of islets – the pancreatic tissue that contains
hormone-producing cells – is one therapy considered for people with type 1
diabetes, who produce little or no insulin because their islets are destroyed by
their own immune systems.
But as with many tissue and organ transplants,
donors are scarce, and there is a strong possibility that the transplantation
The well-developed blood vessel network built into the
engineered tissue is key to its success, the researchers concluded. The blood
vessels encourage cell-tocell communication, by secreting growth hormones and
other molecules that significantly improve the odds that transplanted tissue
will survive and function normally.
The findings confirm that the blood
vessel network “provides key survival signals to pancreatic, hormone-producing
cells even in the absence of blood flow,” Levenberg and colleagues wrote. One
reason transplants fail, Levenberg said, “is that the islets are usually
transplanted without any accompanying blood vessels.”
Until the islets
begin to connect with a person’s own vascular system, they are vulnerable to
oxygen and nutrient starvation.
The 3-D system developed by the Technion
researchers tackled this challenge by bringing together several cell types to
form a new transplantable tissue.
Using a porous plastic material as the
scaffold for the new tissue, the scientists seeded the scaffold with mouse
islets, tiny blood vessel cells taken from human umbilical veins, and human
foreskin cells that encouraged the blood vessels to develop a tube-like
Islets grown in these rich, multicellular environments lived
three times as long on average as islets grown by themselves, Levenberg and
The technology “is still far from tests in humans,”
Levenberg said, but she noted that she and her colleagues are beginning to test
the 3-D tissue scaffolds using human instead of mouse islets.
advantages provided by this type of environment are really profound,” said
Xunrong Luo, an islet transplantation specialist at the Northwestern University
Feinberg School of Medicine in Chicago. She noted that the number of islets used
to lower blood sugar levels in the mice was nearly half the number used in a
typical islet transplant.
According to the Northwestern researcher, the
3-D model demonstrated in the study “will have important and rapid clinical
implications” if the results can be replicated with human cells. “This model
system also provides a good platform to study the details and mechanisms that
underlie successful transplantation.”
Meanwhile, other islet research
relevant to both type I and type II diabetes is being conducted by Dr. Eli
Lewis, a member of the Clinical Biochemistry and Pharmacology department at BGU
and the head of Israel’s only clinical islet lab.
In a recent report,
Lewis, working with doctoral students Eyal Ozeri, Mark Mizrahi and Galit Shahaf,
addressed the immune system that arrives at the grafted islets. The team
examined cells relevant for the early response of the immune system. These
so-called dendritic cells normally collect molecules from the site of the graft
and deliver them to the draining lymph nodes for presentation to the
graft-recipient’s lymphocytic cells.
The group found that the naturally
occurring protein alpha1-antitrypsin (AAT) employs these cells for the purpose
of elevating the levels of regulatory protective T cells and thereby affords
critical protection to islet grafts. According to the experiments, AAT causes
dendritic cells to advance from immature to semi-mature, instead of completing
their final T cell-activating mature phenotype.
At this point a crucial
question was raised: Do these semimature dendritic cells have the ability to
migrate to the draining lymph nodes? After all, if they fail to migrate, they
won’t be able to alter the course of the immune system in favor of the islet
The group unexpectedly noticed that in detailed migration
experiments in the presence of AAT treatment – both in cultures and in whole
animals – not only do the dendritic cells display migratory capabilities, but
they actually migrate faster.
One of the implications of these findings
relates to current immunosuppressive treatment protocols that do not afford the
fine control of the immune system toward a favorable outcome, such as observed
in the current study.
The approaches developed by these two Israeli
research groups hold an intriguing practical scientific overlap. When an organ
graft, such as kidney, is connected to the recipient’s blood supply, a rapid
entry of the immune system occurs such that gravely injures the graft. Islets,
paradoxically, benefit in this respect from some spatial separation from
blood-borne immune cells in that they are non-vascularized upon engraftment.
With their vascularization enhanced by the Technion group, an answer to the
aggressive immune system can be found in the work performed at BGU.