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Stem Cells and Diabetes:
New Trends and Clinical Prospects
By Juan Domínguez-Bendala, Ph.D. and Camillo Ricordi, M.D.
ype I diabetes has been acknowledged,
T from very early on, as one the top
potential targets of stem cell-based
regenerative therapies. While the treatment of
other diseases would typically require extensive
bioengineering and/or the recapitulation of a
rather complex cellular niche, the case for type I
diabetes was solidly grounded on the fact that, in
principle, replacement was needed for only one
cell type – the insulin-producing beta cell. A
tremendous body of work spanning decades of
basic and clinical research had established that
beta cells can exert glycemic control in a variety of
ectopic locations, effectively simplifying the
problem. Finally, successful clinical therapies
resulting in insulin-independence (islet transplan-
tation) had already been in use for two decades,
demonstrating the feasibility of cell-based
approaches for type I diabetes. However, a
decade after the isolation of the first human
embryonic stem (huES) cells, other a priori less-
likely targets seem to have taken an early lead in
the race to clinical applications. Informally
organized in “top stories”, this article will review
the reasons behind this apparent paradox,
describing the not-so-simple nature of the
problem, the most promising avenues of research,
and the challenges that still lie ahead.
Islet Transplantation: The Proof of Concept
Pancreatic transplantation is effective at eliminating the need for
exogenous insulin in type I diabetic patients1, but the limitations
common to all solid organ transplantation procedures (including
scarcity of donors and complications inherent to major surgery2-7)
make it hardly a therapy of choice. Islet transplantation, in contrast,
is a much less invasive approach that allows for the selective
heterotopic engraftment of the small percentage of pancreatic cells
that secrete insulin.8-13 Two major breakthroughs shaped the history of
this practice after the first tentative attempts in the late 70s and early
80s. The first one was the invention of a semi-automated method for
the isolation of islets from a donor pancreas, which led to dramatic
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73
yield increases and the first reports on insulin independence in
humans.14 The second was the development of a steroid-free
immunosuppresive regime that helped preserve the survival of
engrafted islets, extending their function for 5 years or longer in a
significant percentage of transplanted patients.15,16 In short, the
procedure is based on the enzymatic/mechanical dissociation of islets
from the pancreatic parenchyma, using a digestion chamber shaken
at a pre-determined speed. Once the digestion is completed, islet cell
clusters are separated by gradient centrifugation and then cultured
and infused in the liver of the patient via the portal vein. Islets are
known to lodge in the pre-sinusoidal capillaries of the liver, where
they get revascularized within weeks of the procedure.9,11,12,17,18 If
carried out by skilled teams, the procedure has a very low incidence
of complications, resulting in immediate blood glucose control15 and
a significant improvement in the patient’s quality of life.19
Despite the continued refinements of the technique, to this day
islet transplantation remains a “brute force” approach. The digestion
and isolation procedure may destroy one half of the islets present in
any given donor pancreas; and by some estimates, up to 80% of those
that are infused may also die within hours of the procedure.20 By this
account, the observation that 5 years later only 10-50% of the
patients are off-insulin15,21 is not as surprising as the fact that up to
80% are insulin-independent 1 year after the procedure.15 In
summary, our clinical experience is that even very little can go a long
way, which bodes well for the applicability of stem cell therapies to
treat this disease.
To avoid redundancy with other articles in this publication, we
will spare the reader yet another introduction on the basics of stem
cells, its many types and prospective uses, proceeding instead to
describe progress in their use for the treatment of diabetes. In no
particular order of importance, here are some of the most significant
advances reported over the last couple of years that are likely to shape
the overall direction of the field:
Functional Beta-like Cells Derived From
huES Cells.
In a triad of groundbreaking communications, the Novocell
team led by E. Baetge described in quick succession a method for the
efficient generation of definitive endoderm from huES cells22, the first
report on “canonical” huES cell differentiation into beta-like cells23
and, finally, a convincing demonstration of in vivo maturation and
function of huES cell-derived pancreatic progenitors.24 The latter
approach was designed to address the fact that the in vitro protocol,
for all its virtues, was highly inefficient (less than 10% of insulin-
producing cells) and did not result in measurable glucose-stimulated
insulin release. The rationale for transplanting immature progenitors
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was that perhaps the in vivo microenvironment would provide them
with the necessary cues to complete their differentiation into
functional beta cells. Success was achieved at the expense of a rather
long lag period till function (up to three months) and a very high
incidence of teratomas, which would obviously hamper the clinical
translation of this method.25 It is unclear at this point the direction
the field will take. On the one hand, the full differentiation protocol
has been reportedly difficult to reproduce with cell lines other than
those indicated in the original articles, which would argue in favor of
additional research into developing more robust methods that could
be used with many cell lines. Few would dispute that a fully
functional, ready-to-transplant cell product would be preferable in a
clinical setting -not only because of the expected reduction in the rate
of tumorigenic events, but also because of the elimination of the lag
between transplantation and function. In this context, other
competing methods26 may still prove more viable than Novocell’s. On
the other hand, progress at sorting out the fully mature cells from the
carry-over undifferentiated ones, together with the development of
appropriate encapsulation techniques and better controls to identify
a teratogenic threshold, may still allow for an early therapeutic
implementation of the in vivo maturation approach.
Directed Differentiation of iPS Cells.
Nothing epitomizes better the frantic pace of stem cell research
than the advent and overnight success of induced pluripotent stem
(iPS) cells. Barely two years after the first breakthrough reports on the
reprogramming of adult fibroblasts by viral transduction of a few
master genes27,28, this technique -which allows for the generation of
custom-made, patient-matched embryonic stem (ES)-like cells- has
almost relegated to oblivion the much more cumbersome theoretical
alternative of somatic cell nuclear transfer (SCNT) for “therapeutic
cloning”.29,30 The biotechnological feat of reprogramming adult
somatic cells in such simple fashion is likely to have enormous
medical implications, provided that (a) the newly reprogrammed cells
are comparable to blastocyst-derived ES cells; and (b) the procedure
can be done safely. Despite some reports indicating that the
molecular signature of iPS cells might be, after all, somewhat
different to that of ES cells31, there is very little question now that
both pluripotent stem cell types are, to a large extent,
interchangeable. As for the safety concerns, ongoing efforts at
addressing them include the use of non-viral delivery methods32,
episomal vectors33, protein transduction34,35, the progressive
replacement of reprogramming genes by chemical factors36-39 and the
use of adult stem cells as substrates for reprogramming.40
As these techniques quickly became mainstream, laboratories
around the world endeavored to replicate with iPS cells results
previously attained with huES cells.41-43 In this context, the eventual
use of these cells for direct differentiation into beta-like cells was
nothing short of inevitable. The first report was published last year by
Tateishi and colleagues44, who drove skin-derived iPS cells along the
beta cell lineage using a protocol similar to that described by Jiang et
al 26 for huES cells.
The fact that type I diabetes is an autoimmune disorder certainly
limits enthusiasm for the prospective uses of patient-matched iPS
cells. After all, since the patient’s immune system is already poised to
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destroy its own beta cells, immunosuppresion would still be necessary
no matter the origin of the replacement. It can be argued, however,
that effective iPS-to-beta cell differentiation methods could lead to
therapies that would tackle two out of the three major problems we
face right now (supply and allorejection), singling out autoimmunity
as the only remaining hurdle. This would simplify the problem,
allowing for a much more effective use of resources to find a cure to
the disease.
Infusion of Bone Marrow Stem Cells for
Type I Diabetes?
It has been hypothesized that some adult stem cells (chiefly of
the ubiquitous mesenchymal lineage, obtained from the bone
marrow and other locations) might contribute to the regeneration of
pancreatic beta cells if delivered either systemically or locally. The
potential benefits of this approach are clear inasmuch as these cells are
proliferative enough to yield therapeutic loads, can be potentially
obtained from the patient, and pose no ethical concerns. On the
other hand, premature claims that mesenchymal stem cells (MSCs)
cells are a safer, non-tumorigenic alternative to huES and iPS cells
have proven wrong. Indeed, their adaptation to in vitro culture can
lead to the development of chromosomal abnormalities resulting in
malignant transformation as early as in a few passages.45-50 Also, the
mesodermal origin of both MSCs and hematopoietic places a big
question mark on their purported ability to become endodermal
tissues such as pancreatic beta cells. Early observations that donor
bone marrow cells could migrate to the damaged pancreas and
contribute to the regeneration of islets51 were subsequently disputed
by studies that confirmed the migration but not the differentiation.52-54
The latter of such studies, in fact, provided evidence that the cells
recruited to the pancreas were rather of endothelial origin. As is the
case with MSCs -which have well-documented trophic, angiogenic,
immunomodulatory and anti-inflammatory effects55-61, these
mobilized bone marrow-derived cells could indeed aid in the
endogenous regeneration of beta cells, but not by direct
differentiation.
Whichever the mechanism may be, autologous intra-pancreatic
bone marrow transplantation is currently enjoying the limelight as a
potential new treatment for type I and II diabetes. Much of this
attention is due to the controversial for-profit clinical practice of the
technique in some countries at a time when there is no evidence of
safety and efficacy in humans. Fortunately, there are already a number
of Phase I/II trials looking at the potential benefit of local delivery of
MSCs and bone marrow cells (www.clinicaltrials.gov), including one
in the USA for type II diabetes in which autologous intra-pancreatic
bone marrow cell transplantation is done in conjunction with
hyperbaric treatment. The role of oxygen in promoting beta cell
differentiation and survival has been recently established62-64, and
preliminary results of this combination therapy in human subjects are
highly encouraging.65
Resetting the Immune System?
Most people tend to think about stem cells as “building blocks”
to be used for the repair of damaged tissues. We have described above
how bone marrow stem cells may actually help in the regeneration of
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islets by providing endogenous progenitor cells with the chemical
cues required to complete their maturation, or by otherwise
supporting their action (e.g., by creating anti-inflammatory or
angiogenic microenvironments). One of the major developments in
the field over the past few years has to do with another well-known
facet of bone marrow stem cells, namely their ability to modulate the
body’s immune response. Thus, in clinical trials conducted on 15
newly diagnosed type I diabetic patients, hemaotopoietic stem cells
were mobilized, harvested from peripheral blood and subsequently
frozen for later use. Following a harsh immunosuppressive treatment
intended to destroy autoreactive T cell clones, the patients were then
reinfused with their own cryopreserved hematopoietic stem cells,
which were assumed to be “naïve” (i.e., at a stage prior to the onset of
the disease). In the first communication, the authors reported that 14
out of the 15 patients became insulin-free for extended periods of
time.66,67 A recent update of the original study with a longer follow-
up (21/2 years) confirmed that C-peptide levels increased significantly
in the treated patients, the majority of whom achieved and
maintained insulin independence.68 Excitement was and remains
justified, as such reports are the first ever suggestive of a definitive
“cure”. However, the approach also has substantive limitations. For
one, it has been hypothesized to work only in recently diagnosed
patients, who may still have a significant mass of beta cells susceptible
of regeneration. If such mass is below a still undetermined threshold
(as would be expected in long-standing diabetes), it may still be
necessary to supplement the patients with an exogenous “boost” of
beta cells. Secondly, the immunosuppressive regime is highly toxic,
and potentially fatal. Although no deaths have been reported yet in
relation to this therapy, the sample sizes are still very small. A 2005
study evaluating the clinical outcome of autologous hematopoietic
stem cell transplantation for a variety of autoimmune conditions
(including neurological, rheumatologic, hematological and
gastrointestinal disorders) concluded that the treatment was effective,
but associated with a high rate of morbidity and mortality (7% at 3
years).69 However, better patient selection, refinement of methods,
and progressive experience of teams are likely to decrease transplant-
related mortality to more acceptable rates.
Regeneration: From The Duct to Replication
(And Back?)
Proof of the rapid evolution of an ever-changing field is the
continuous shift of the paradigm on adult beta cell regeneration. It
was the conventional wisdom for decades that beta cells arose from
progenitor cells residing in the pancreatic ducts, although the support
for this hypothesis had always been anecdotal and largely based on
two-dimensional pictures of beta cells seemingly budding out from
the periductal area.70 A series of elegant lineage-tracing experiments
conducted in a transgenic mouse model challenged this notion in
2004, indicating that self-replication was the main mechanism
behind adult beta cell turnover and regeneration.71 While the
proponents of the “adult stem cell” theory still contended that human
beta cell regeneration might obey to different rules, these clear-cut
observations clearly put the burden of proof on their shoulders. Then
the new idea was challenged again in 2008, first by new lineage
tracing experiments showing ductal offspring in newly created
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islets72 and then by the unexpected finding that the Ngn3 endocrine
differentiation program could be reactivated in the adult pancreas
following partial duct ligation.73 The physiological significance of this
model is unclear, and it is a safe assumption that self-replication is still
the main engine of adult beta cell regeneration. However, now we
know that the pancreas may still have an “ace in the hole”, an
alternative pathway that could be activated under specific
circumstances and take over regeneration. Further research will be
needed to decipher its molecular determinants, the reasons that make
this regeneration model different from all the others (which do not
induce the Ngn3 program) and the potential ways to apply such
knowledge to our advantage for therapeutic purposes.
Transdifferentiation
Also in line with the above strategy, a subtler but equally effective
method to induce beta cell neogenesis in the adult pancreas was
recently reported by Zhou and colleagues74, who described the
“reprogramming” of the acinar tissue of the murine pancreas by
ectopically expressing a combination of three genes, namely Pdx1,
Ngn3 and MafA. New insulin-producing cells – virtually
indistinguishable from the native ones- were detected just days after
the adenoviral delivery of the aforementioned cassettes, and kept
expanding long after the viruses had been cleared from the host.
Clearly inspired in the pioneering work of Ferber and colleagues
in the liver75-77, the new approach had the advantage that -perhaps due
to the closeness of the starting material to the desired end product-
the reprogramming process completely abrogated the original
phenotypes; in other words, these were true beta cells, not merely
exocrine cells that secreted insulin. Hyperglycemia was significantly
ameliorated in the treated animals, even if diabetes was not
completely reversed. This could be due to the fact that, while direct
communication between beta cells appears to be critical for the
synchronicity and effectiveness of glucose-mediated insulin
secretion78,79, the newly induced cells failed to aggregate in clusters.
The clinical applicability of this strategy is still unclear. Although
adenoviruses are present in the recipient only transiently, they are
known to elicit serious immune responses. However, these
experiments are proof of principle that exocrine cell reprogramming
is feasible and perhaps doable ex vivo on cultured acinar cells that
would be subsequently transplanted. Non-viral alternatives (such as
the use of chemicals and/or protein transduction) should also be
explored with the goal of improving the safety of this promising
approach, thus accelerating its clinical translation.
New trends in transplantation
Although the liver has served as the surrogate for the pancreas for
all islet transplantation procedures conducted in humans thus far,
there is widespread consensus that this ectopic location is far from
optimal. As mentioned earlier in this article, islets sustain a massive
cell loss upon intra-hepatic infusion. Stem cell-derived beta cells
(whichever their origin) are likely to share the same fate, unless
alternative sites are identified. There has been an active search of such
sites in recent years, including an intriguing approach pioneered by
Speier and colleagues in Miami80 by which islets transplanted in the
anterior chamber of the eye can restore normoglycemia in diabetic
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mice while allowing for a real-time, in vivo follow-up of their
engraftment, vascularization and response to the immune attack.
Unfortunately, the generalized view of the eye as an
immunoprivileged site81 has not proven true for islet transplantation.
This, together with the rather limited load of islets that could be
transplanted in a clinical setting, makes the eye an unlikely candidate
to replace the liver as a preferred location.
An alternative to finding a suitable site is to create one. Thus,
Pileggi et al82 demonstrated recently that islets infused into a
biocompatible, subcutaneously implanted device – previously
allowed to vascularize through its stainless-steel mesh walls – were
able to reverse hyperglycemia in diabetic rats. The advantages of such
an approach are many-fold: first, the islets (or the stem cell-derived
beta cells) would not spread throughout an entire organ, as they
Juan Domínguez-Bendala, Ph.D.
Juan Domínguez-Bendala is Director of
the Pancreatic Development & Stem Cells
laboratory at the Diabetes Research
Institute, University of Miami. He
obtained his Ph.D. at the Roslin Institute
(UK) under the supervision of Dr.
McWhir, co-author of the 1997 report on
Camillo Ricordi, M.D.
Camillo Ricordi, M.D., is Professor of
Surgery, Medicine, Biomedical
Engineering, Microbiology and
Immunology, Director of the Cell
Transplant Center and head of the
Diabetes Research Institute at the
University of Miami. Dr. Ricordi is
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currently do when infused through the portal vein. This would enable
the clinician to better monitor the graft while minimizing the
inflammatory responses. Secondly, the use of these devices may
eventually allow for the administration of immunosuppresants locally
at much smaller effective doses than those required if taken
systemically. This would largely prevent the occurrence of the side
effects associated with oral immunosuppresion83. Finally, if using
huES/iPS cell-derived tissues as a source of insulin-producing cells,
any teratogenic lesion potentially arising from carryover
undifferentiated cells would be contained within the device.
Acknowledgements
CR and JDB are funded by the NIH, JDRF and the Diabetes
Research Institute Foundation (DRIF).
the cloning of Dolly the sheep. During his training, he acquired
considerable experience in ES cell research and state-of-the-art
genetic engineering techniques. His current projects focus on the use
of stem cells to obtain pancreatic islets. He co-invented the “oxygen
sandwich”, a culture device designed to promote differentiation. He
is also working on long-term culture/regeneration of pancreatic stem
cells and reprogramming.
known for developing the method for large scale isolation of human
pancreatic islets, and for leading the team that performed the first
series of successful clinical islet allografts in 1990. Dr. Ricordi’s
research interests include induction of immune tolerance, cellular
therapies, stem cells and regenerative medicine strategies. Dr. Ricordi
received numerous honors and awards, authored over 600 scientific
publications and, as inventor, holds nine patents.
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