Immunology,
Endocrine & Metabolic Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Immunology, Endocrine
and Metabolic Agents')
ISSN: 1871-5222
Immunology, Endocrine &
Metabolic Agents in Medicinal Chemistry
Volume 6, Number 2, April 2006
Contents
Islet Transplantation: Hopes and Hurdles
Guest Editor: Göran Mattsson
Editorial Pp.
137
Advances and Barriers in Mammalian Cell Encapsulation
for Treatment of Diabetes Pp. 139-153
P. de Vos, A. Andersson, S.K. Tam, M.M. Faas and J.P.
Hallé
[Abstract]
Therapeutic Angiogenesis for Islet Revascularization
Pp. 155-166
N. Zhang, S. Bertera, S. Qu, J. He, D. Su, R. Bottino,
J. Bromberg and H.H. Dong
[Abstract]
Physiology of Islet Engraftment Pp. 167-178
C. Kampf and P-O. Carlsson
[Abstract]
The Role of c-Myc in Beta Cell Mass Homeostasis
Pp. 179-189
G. Mattsson, S. Pelengaris and M. Khan
[Abstract]
A Perspective on Clinical Islet Transplantation: Past,
Present and Developments for Future Pp. 191-208
M. Mirbolooki, A.M.J. Shapiro and J.R.T. Lakey
[Abstract]
Induction and Amelioration of Environmental Stress
in Isolated Islets Until Transplantation Pp. 209-218
D. Brandhorst, H. Brandhorst and T. Linn
[Abstract]
Sources of β-Cells for Cell Therapy in Diabetes
Pp. 219-231
H. Baharvand, E. Roche and B. Soria
[Abstract]
Abstracts
[Back to top]
Editorial
Ever since Paul Langerhans described characteristic cell
clusters in the pancreas in 1869, they have been the subject
of a vast amount of research, mainly focusing on finding a
cure for diabetes. Since the number of patients with diabetes
is rapidly increasing and is estimated to reach 150-220 million
worldwide by the year 2010, this topic is becoming increasingly
important. Over the last few years, the transplantation of
islets has become a realistic option for the treatment of
selected patients with type 1 diabetes mellitus. However,
even though progress has been made, there are still hurdles
to overcome before a definite cure for every individual suffering
from type 1 diabetes can be provided. Inadequate supplies
of insulin producing cells, poor post-transplantation performance
of the islets, and the requirement of life-long treatment
of patients with immunosuppressive drugs are some of the challenges
that clinicians and researchers face. In view of this, I am
very honoured and pleased to have some of the leading research
groups in the field of diabetes research contributing to this
themed issue of islet transplantation; hopes and hurdles.
The latest news on a diverse range of topics including fascinating
articles regarding islet isolation, clinical islet transplantation,
stem cells and angiogenesis are published in this special
issue.
At last, I sincerely hope that you enjoy the articles provided
in this themed issue and that we can someday say that we have
won the battle against diabetes mellitus.
Göran Mattsson, PhD
Guest Editor
Department of Medical Cell Biology
Uppsala University; Biomedical Centre
Husargatan 3, Box 571
SE-751 23 Uppsala; Sweden
E-mail: goran.mattsson@medcellbiol.uu.se
[Back to top]
Advances and Barriers in Mammalian Cell Encapsulation
for Treatment of Diabetes
P. de Vos, A. Andersson, S.K. Tam, M.M. Faas and J.P.
Hallé
Mammalian cell encapsulation is under investigation for the
treatment of a wide variety of diseases, since it allows for
transplantation of endocrine cells in the absence of undesired
immunosuppression. The technology is based on the principle
that transplanted tissue is protected for the host immune
system by an artificial membrane. In spite of the simplicity
of the concept, progress in the field of immuno-isolation
has been hampered. During the past two decades, three major
approaches of encapsulation have been studied. These include
(i) intravascular macrocapsules, which are anastomosed to
the vascular system as AV shunt, (ii) extravascular macrocapsules,
which are mostly diffusion chambers transplanted at different
sites, and (iii) extravascular microcapsules transplanted
in the peritoneal cavity. The advantages and pitfalls of the
three approaches are discussed and compared in view of applicability
in clinical islet transplantation. At present, microcapsules,
due to their spatial characteristics, offer better diffusion
capacity than macrocapsules. During the past five years, important
advances have been made in the knowledge of the characteristics
and requirements capsules have to meet in order to provide
optimal biocompatibility and survival of the enveloped tissue.
Novel insight shows that islet-cells themselves and not the
capsule materials should be held responsible for loss of a
significant portion of the immuno-isolated islet cells and,
thus, failure of the grafts on the long term. New approaches
in which newly discovered inflammatory responses are silenced
bring the technology of transplantation of immunoisolated
cells close to clinical application.
[Back to top]
Therapeutic Angiogenesis for Islet Revascularization
N. Zhang, S. Bertera, S. Qu, J. He, D. Su, R. Bottino,
J. Bromberg and H.H. Dong
Successful islet transplantation depends on the infusion
of sufficiently large quantities of islets, requiring multiple
pancreas donors per recipient. Unfortunately, more than 70%
of functional islet mass are lost in the early post-transplantation
phase. Unlike whole-organ transplantation by which grafts
are implanted as vascularized tissue, islets are transplanted
as single islets or islet clusters that are considered avascular.
As a result, microvascular perfusion to newly transplanted
islets does not resume immediately after transplantation and
can take up to weeks until the reestablishment of a functional
microvasculature within islet grafts. Delayed and insufficient
islet revascularization can deprive newly transplanted islets
of oxygen and nutrients, resulting in islet cell death and
contributing to early graft failure. There is mounting evidence
that impaired islet revascularization constitutes an independent
factor that reduces the viability and compromises the function
of transplanted islets, thereby limiting the success rate
of islet transplantation. In this article, we will review
the most recent advances made in deciphering the underlying
mechanism of islet revascularization and exploring therapeutic
strategies for enhancing islet revascularization and preserving
functional islet mass in diabetic recipients.
[Back to top]
Physiology of Islet Engraftment
C. Kampf and P-O. Carlsson
Pancreatic islet transplantation is a tempting strategy to
treat patients with type 1 diabetes mellitus, since if successful
it could provide a cure for the disease. At present, there
is, however, a poor long-term outcome of such transplantations
compared to the results for whole pancreas transplantation.
One explanation for this may be inadequate engraftment of
the transplanted cells in the new microenvironment. The engraftment
process includes immediate survival in the post transplantation
phase. There is likely extensive cell death immediately following
transplantation mainly due to inflammatory responses triggered
by e.g. hypoxia. Also the long-term survival and function
of the transplanted islets is encompassed by the term engraftment.
This is influenced by the cellular turn-over rate, and the
degree of revascularization and reinnervation of the islet
tissue. To regain optimal function in surviving cells, new
vascular and nervous systems similar to those in endogenous
islets need to form. Both qualitative and quantitative changes
compared to endogenous islets have, however, been described
in the new vascular system that develops following transplantation,
and these changes seem to have consequences for islet blood
perfusion, metabolism and function. Comparatively little is
known regarding the extent of functional re-growth of nerves
that occurs, and its influence on graft function. This review
also discusses the challenges of engraftment that seem specific
for intraportally transplanted islets, e.g. the instant blood
mediated immune reaction, the loss of glucagon response to
hypoglycemia, and the lower β-cell
proliferation rate in intraportally transplanted islets than
in islets grafted to the kidney.
[Back to top]
The Role of c-Myc in Beta Cell Mass Homeostasis
G. Mattsson, S. Pelengaris and M. Khan
Reduced β-cell
numbers and function (β-cell
failure) contribute to essentially all forms of diabetes,
and must be corrected if established disease is to be cured.
Current therapies have been shown not to prevent β-cell
failure and the availability of insulin-secreting cells for
replacement-based therapies is severely restricted. Researchers
have responded to this challenge by aiming to generate new
β-cells
(or β-like
cells) in vitro or potentially in situ,
by diverse strategies including manipulation of stem cells,
β-cells,
or even non-β-cells
such as hepatocytes. Which ever approach is ultimately most
successful is at present not known, what is certain is that
progress will needs to be informed by a deeper understanding
of those cellular processes which determine β-cell
differentiation, renewal and survival. Interest in this approach
has been fuelled by the remarkable capacity for β-cell
replication and renewal demonstrated in many model systems.
Potential regulatory factors have already been identified
and include various proteins required for promoting the G1/S
transition of the cell cycle, including c-Myc and downstream
transcriptional targets such as cyclin D and E2F family members.
It is likely that for these factors to be exploited therapeutically,
that we will need to circumvent the inherent tumor suppressor
activity associated with aberrant activity of these proteins,
including avoidance of apoptosis and growth arrest. Much recent
work has begun to unravel the complexity of growth-regulating
networks in which these proteins are involved and there is
reason for future optimism.
[Back to top]
A Perspective on Clinical Islet Transplantation: Past,
Present and Developments for Future
M. Mirbolooki, A.M.J. Shapiro and J.R.T. Lakey
Accelerated developments and improved understanding of the issues that face
clinical islet cell transplantation during the last 20 years
have led this simple concept to a successful treatment for
diabetes. Islet cell transplantation involves the extraction
of islets of Langerhans from organ donors through complex
digestion and purification processes. After implantation in
patients with type-1 diabetes, the treatment can provide near
perfect, moment-to-moment control of blood glucose, far more
effectively than injected insulin. The procedure offers the
benefits of whole pancreas transplantation, but with less
risk. Since the introduction of “Edmonton Protocol”,
significant advances in islet isolation techniques and purification
technology, novel immunosuppressants and tolerance strategies
have renewed interest in clinical islet transplantation for
the treatment of diabetes mellitus. The "Edmonton Protocol"
has been successfully replicated by other centers in an international
multicenter trial. A number of key refinements in pancreas
transportation, islet preparation and newer immunological
conditioning and induction therapies have led to continued
advancement through extensive collaboration between key centers.
This article provides an overview of the history of islet
transplantation followed by discussion on current controversies
of donor selection, pancreas procurement, hypothermic preservation
solutions, current islet isolation technique, islet transplantation
procedure, post transplantation immunology, and developments
for future.
[Back to top]
Induction and Amelioration of Environmental Stress
in Isolated Islets Until Transplantation
D. Brandhorst, H. Brandhorst and T. Linn
Pancreatic tissue, processed for subsequent clinical islet
transplantation, is exposed to enormous biophysical and biochemical
stress causing injury and death in a large number of islets
even before they are transplanted. Since several steps within
this heterogenous process are associated with non-physiologic
and harmful ambient conditions the damaging mechanisms are
attributed to four different determinants: 1) brain death
in the organ donor, 2) insufficient oxygen supply during pancreas
procurement, isolation processing, culture and after intraportal
transplantation, 3) destruction of the natural environment
during isolation, and 4) exposure to toxic reagents during
the isolation process. Potential strategies to ameliorate
the detrimental impact of these factors on the quality of
subsequently transplanted islets are discussed.
[Back to top]
Sources of β-Cells for Cell Therapy in Diabetes
H. Baharvand, E. Roche and B. Soria
Diabetes affects an estimated 150 million people worldwide,
being the most prevalent metabolic disorder. The pathology
is characterized by a selective destruction of pancreatic
β-cells
and is divided into two main types: type 1 and type 2. Type
1 diabetes results from an autoimmune-mediated destruction
of insulin-producing β-cells.
Type 2 diabetes is a more complex pathology, presenting a
progression from insulin resistance in peripheric tissues
(muscle and adipose) to a fail use in β-cell
function and insulin secretion, culminating in the activation
of apoptotic mechanisms and β-cell
death. In this context, scientists are proposing novel therapeutic
strategies that might allow perfect glycemic control for most
patients with diabetes. Embryonic stem cells are pluripotent
cells derived from the inner cell mass of blastocysts. Adult
stem cells are committed cells present in certain niches located
in adult tissues and responsible for tissue repair and regeneration.
Recently, the development of appropriate culture conditions
for the differentiation of these cells into specific fates
has permitted their use as potential therapeutic agents for
several diseases. The therapeutic potential of transplantation
of insulin-secreting pancreatic β-cells
has stimulated the interest in using stem cells as a starting
material from which to generate insulin secreting cells
in vitro. Insulin-producing cells derived from stem cells
have been shown to reverse experimentally induced diabetes
in animal models. This review will summarize the different
approaches that have been used to obtain insulin-producing
cells from stem cells by focussing on key points that will
allow in vitro differentiation and subsequent transplantation
on the future.
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