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Current
Stem Cell Research & Therapy
ISSN: 1574-888X
Current Stem
Cell Research & Therapy
Volume 1, Number 2, May 2006
Contents
Current Progress with Primate Embryonic Stem Cells Pp.
127-138
James A. Byrne, Shoukhrat M. Mitalipov and Don P. Wolf
[Abstract]
Embryonic Stem Cells: Hepatic Differentiation
and Regenerative Medicine for the Treatment of Liver Disease
Pp. 139-156
Kinji Asahina, Kenichi Teramoto and Hirobumi
Teraoka
[Abstract]
Adult Stem Cells: The Therapeutic Potential of
Skeletal Muscle Pp. 157-171
Amarjit Saini and Claire E.H. Stewart
[Abstract]
Growth and Differentiation of Human Embryonic
Stem Cells for Cardiac Cell Replacement Therapy Pp.
173-187
Chunhui Xu, Jane Lebkowski and Joseph D. Gold
[Abstract]
Mobilization and Harvesting of Peripheral Blood
Stem Cells Pp. 189-201
Rainer Moog
[Abstract]
Acute Graft-Versus-Host Disease–Challenge
for a Broader Application of Allogeneic Hematopoietic Cell
Transplantation Pp. 203-212
Robert Zeiser, Andreas Beilhack and Robert S.
Negrin
[Abstract]
Repair of Injured Articular and Growth Plate Cartilage
Using Mesenchymal Stem Cells and Chondrogenic Gene Therapy
Pp. 213-229
Cory J. Xian and Bruce K. Foster
[Abstract]
Therapeutic Use of Limbal Stem Cells Pp.
231-238
Avni Murat Avunduk and Yavuz Tekelioglu
[Abstract]
Non-HLA Gene Polymorphisms and the Outcome of
Allogeneic Hemato-poietic Stem Cell Transplantation Pp.
239-253
Katarzyna Bogunia-Kubik, Barbara Wysoczanska
and Andrzej Lange
[Abstract]
Diabetes Mellitus: A Potential Target for Stem
Cell Therapy Pp. 255-266
Christopher J. Burns, Shanta J. Persaud and Peter M. Jones
[Abstract]
Mechanisms of Neural Stem Cell Fate Determination:
Extracellular Cues and Intracellular Programs
Pp. 267-277
Masahiko Abematsu, Ian Smith and Kinichi Nakashima
[Abstract]
Abstracts
[Back to top]
Current Progress with Primate Embryonic Stem Cells
James A. Byrne, Shoukhrat M. Mitalipov and Don P. Wolf
Embryonic stem cells (ESCs) can proliferate indefinitely,
maintain an undifferentiated pluripotent state and differentiate
into any cell type. Differentiation of ESCs into various specific
cell-types may be able to cure or alleviate the symptoms of
various degenerative diseases. Unresolved issues regarding
maintaining function, possible apoptosis and tumor formation
in vivo mean a prudent approach should be taken towards
advancing ESCs into human clinical trials. Rhesus macaques
provide the ideal model organism for testing the feasibility,
efficacy and safety of ESC based therapies and significant
numbers of primate ESC lines are now available. In this review,
we will summarize progress in evaluating the genetic and epigenetic
integrity of primate ESCs, examine their current use in pre-clinical
trials and discuss the potential of producing ESC-derived
cell populations that are genetically identical (isogenic)
to the host by somatic cell nuclear transfer.
[Back to top]
Embryonic Stem Cells: Hepatic Differentiation and
Regenerative Medicine for the Treatment of Liver Disease
Kinji Asahina, Kenichi Teramoto and Hirobumi
Teraoka
Hepatocyte transplantation is considered a potential treatment
for liver diseases and a bridge for patients awaiting liver
transplantation, but its application has been hampered by
a limited supply of hepatocytes. Embryonic stem (ES) cells
established from early mouse and human embryos are pluripotent,
and proliferate indefinitely in an undifferentiated state
in vitro. Since differentiation from ES cells seems
to recapitulate early embryonic development, if hepatocytes
could be efficiently generated in vitro, ES cells
might become a source of transplantable hepatocytes for cell
replacement therapy. Hepatocytes have been generated from
ES cells in vitro, and the hepatocytes differentiated
from ES cells have been found to express many hepatocyte-related
genes and perform hepatic functions. However, it remains unclear
whether the hepatocytes differentiated from ES cells are derived
from definitive endoderm or primitive endoderm. Because visceral
endoderm, which expresses many hepatocyte-related genes, is
derived from primitive endoderm and is fated to form extraembryonic
yolk sac tissues, not to form hepatocytes, ES cells must be
directed to a definitive endoderm lineage in vitro.
This article discusses the differentiation of ES cells into
hepatocytes in vitro in comparison with early embryogenesis,
and describes the efficacy of ES cell-derived hepatocyte transplantation.
[Back to top]
Adult Stem Cells: The Therapeutic Potential of Skeletal
Muscle
Amarjit Saini and Claire E.H. Stewart
Embryonic stem cells have revolutionised our understanding
of normal and deregulated growth and development. The potential
to produce cells and tissues as needed offers enormous therapeutic
potential. The use of these cells, however, is accompanied
by ongoing ethical, religious and biomedical issues. The expansion
potential and plasticity of adult stem cells have therefore
received much interest. Adult skeletal muscle is highly adaptable,
responding to both the hypertrophic and degenerative stresses
placed upon it. This extreme plasticity is in part regulated
by resident stem cells. In addition to regenerating muscle,
if exposed to osteogenic or adipogenic inducers, these cells
spontaneously form osteoblasts or adipocytes. The potential
for and heterogeneity of muscle stem cells is underscored
by the observation that CD45+ muscle side population cells
are capable of reconstituting bone marrow in lethally irradiated
mice and of contributing to neo-vascularisation of regenerating
muscle. Finally, first attempts to replace infarcted myocardium
relied on injection of skeletal myoblasts into the heart.
Cells successfully engrafted and cardiac function was improved.
Harnessing their differentiation/trans-differentiation capacity
provides enormous potential for adult stem cells. In this
review, current understanding of the different stem cells
within muscle will be discussed as will their potential utility
for regenerative medicine.
[Back to top]
Growth and Differentiation of Human Embryonic Stem
Cells for Cardiac Cell Replacement Therapy
Chunhui Xu, Jane Lebkowski and Joseph D. Gold
Due to the limited proliferation capacity of cardiac cells,
cell replacement therapy has been proposed to restore cardiac
function in patients suffering from ischemic heart disease
and congestive heart failure. However, this approach is challenged
by an insufficient supply of appropriate cells. Because of
their apparent indefinite replicative capacity and their cardiac
differentiation potential, human embryonic stem cells (hESCs)
are potential candidates as sources of cells for cell replacement
therapy. Significant progress has been made in improving culture
conditions of undifferentiated hESCs, and using various methods,
several laboratories have reported the generation of contracting
cardiomyocytes from hESCs in vitro. Application of
these cardiomyocytes to the clinic, however, still requires
substantial experimentation to show that 1) they are functional
in vitro; 2) they are efficacious in animal models
of cardiac injury and disease; 3) they are safe and effective
in human conditions, and 4) a sufficient amount of cardiomyocytes
with expected characteristics can be generated in a reproducible
manner. Here we review and discuss current findings on growth
and differentiation of hESCs, and on characterization, enrichment
and transplantation of hESC-derived cardiomyocytes.
[Back to top]
Mobilization and Harvesting of Peripheral Blood Stem
Cells
Rainer Moog
The use of peripheral blood stem cells (PBSC) as a source
of hematopoietic stem cells is steadily increasing and has
nearly supplanted bone marrow. The present article reviews
mobilization and collection of PBSC as well as its side effects.
Specialized harvesting strategies such as large volume leukapheresis
(LVL) and pediatric PBSC collection are included in this overview.
Under steady state conditions, less than 0.05 % of the white
blood cells (WBC) are CD34+ cells. Chemotherapy results in
a 5 – 15-fold increase of PBSC. Combining chemotherapy
and growth factors increases CD34+ cells up to 6% of WBC.
In the allogeneic setting, granulocyte-colony stimulating
factor is used alone for PBSC mobilization. Several factors
affect the mobilization of PBSC: age, gender, type of growth
factor, dose of the growth factor and in the autologous setting,
patient’s diagnosis, chemotherapy regimen and number
of previous chemotherapy cycles or radiation.
Harvesting of PBSC can be performed with various blood cell
separators using continuous or discontinuous flow technique.
Continuous flow separators allow the processing of more blood
compared with intermittent flow devices resulting in higher
yields of CD34+ cells for transplantation. LVL can be used
to increase the CD34+ yield in patients with low CD34+ pre-counts.
Processing of more blood in LVL is achieved by an increase
of the blood flow rate and an altered anticoagulation regimen.
Specialized strategies were developed for pediatric PBSC collection
considering the main limiting factors, extracorporeal volume
and vascular access.
Adverse events in PBSC collection can be subdivided in apheresis
associated and mobilization associated side effects. Citrate
reactions due to hypocalcemia are frequent during apheresis,
especially in pediatric PBSC collection and LVL. Thrombocytopenia
is often observed in patients after termination of apheresis
due to platelet loss during PBSC harvesting. Muscle and bone
pain are frequent adverse events in allogeneic stem cell mobilization
but are usually tolerated under the use of analgesics. Spleen
enlargement followed by rupture is a serious complication
in allogeneic donors.
[Back to top]
Acute Graft-Versus-Host Disease–Challenge for
a Broader Application of Allogeneic Hematopoietic Cell Transplantation
Robert Zeiser, Andreas Beilhack and Robert
S. Negrin
Allogeneic hematopoietic cell transplanation (aHCT) has
been a successful treatment option for malignant disease based
on the graft-versus-tumor effect. However, the overall clinical
success of aHCT is impaired by the high morbidity and mortality
caused by acute graft-versus-host disease (aGVHD). aGVHD can
also be seen as the major limitation of aHCT for a broader
clinical applicability of this treatment, particularly for
non-malignant disease conditions.
Recent murine studies have shed more light on the kinetics
of aGVHD development by tracking donor T cells in vivo.
These data define two functionally distinct stages in aGVHD
pathogenesis taking place in different anatomical compartments.
The aGVHD initiation phase is confined to T cell areas in
secondary lymphoid organs in contrast to the later aGVHD effector
phase at target sites. This temporal pattern may explain the
clinical observation that when acute aGVHD is clinically overt,
treatment with intensified immunosuppression often remains
ineffective.
This review will focus on the immune-pathogenesis of aGVHD,
conventional and novel treatment strategies including the
removal of naïve T cells, tolerance induction by mesenchymal
stem cells, regulatory T cells, genetic manipulation of donor
cells and the potential of memory T cells for improving immune
reconstitution without aGVHD. A better understanding of the
mechanisms involved in aGVHD pathogenesis might allow for
a broader application of novel stem cell therapies.
[Back to top]
Repair of Injured Articular and Growth Plate Cartilage
Using Mesenchymal Stem Cells and Chondrogenic Gene Therapy
Cory J. Xian and Bruce K. Foster
Injuries to the articular cartilage and growth plate are
significant clinical problems due to their limited ability
to regenerate themselves. Despite progress in orthopedic surgery
and some success in development of chondrocyte transplantation
treatment and in early tissue-engineering work, cartilage
regeneration using a biological approach still remains a great
challenge. In the last 15 years, researchers have made significant
advances and tremendous progress in exploring the potentials
of mesenchymal stem cells (MSCs) in cartilage repair. These
include (a) identifying readily available sources
of and devising appropriate techniques for isolation and culture
expansion of MSCs that have good chondrogenic differentiation
capability, (b) discovering appropriate growth factors
(such as TGF-β,
IGF-I, BMPs, and FGF-2) that promote MSC chondrogenic differentiation,
(c) identifying or engineering biological or artificial
matrix scaffolds as carriers for MSCs and growth factors for
their transplantation and defect filling. In addition, representing
another new perspective for cartilage repair is the successful
demonstration of gene therapy with chondrogenic growth factors
or inflammatory inhibitors (either individually or in combination),
either directly to the cartilage tissue or mediated through
transducing and transplanting cultured chondrocytes, MSCs
or other mesenchymal cells. However, despite these rapid pre-clinical
advances and some success in engineering cartilage-like tissue
and in repairing articular and growth plate cartilage, challenges
of their clinical translation remain. To achieve clinical
effectiveness, safety, and practicality of using MSCs for
cartilage repair, one critical investigation will be to examine
the optimal combination of MSC sources, growth factor cocktails,
and supporting carrier matrixes. As more insights are acquired
into the critical factors regulating MSC migration, proliferation
and chondrogenic differentiation both ex vivo and
in vivo, it will be possible clinically to orchestrate
desirable repair of injured articular and growth plate cartilage,
either by transplanting ex vivo expanded MSCs or
MSCs with genetic modifications, or by mobilising endogenous
MSCs from adjacent source tissues such as synovium, bone marrow,
or trabecular bone.
[Back to top]
Therapeutic Use of Limbal Stem Cells
Avni Murat Avunduk and Yavuz Tekelioglu
Stem cells are defined as relatively undifferentiated
cells that have the capacity to generate more differentiated
daughter cells. Limbal stem cells are responsible for epithelial
tissue repair and regeneration throughout the life. Limbal
stem cells have been localized to the Palisades of Vogt in
the limbal region. Limbal stem cells have a higher proliferative
potential compared to the cells of peripheral and central
cornea. Limbal stem cells have the capacity to maintain normal
corneal homeostasis. However, in some pathological states,
such as chemical and thermal burns, Stevens-Johnson syndrome,
and ocular pemphigoid limbal stem cells fail to maintain the
corneal epithelial integrity. In such situations, limbal stem
cell transplantation has been required as a therapeutic option.
In unilateral disorders, the usual source of stem cells is
the contralateral eyes, but if the disease is bilateral stem
cell allografts have to be dissected from family members or
cadaver eyes. The advent of ex vivo expansion of
limbal stem cells from a small biopsy specimen has reduced
the risk of limbal deficiency in the donor eye. Concomitant
immunosuppressive therapy promotes donor-derived epithelial
cell viability, but some evidences suggest that donor-derived
epithelial stem cell viability is not sustained indefinitely.
Thus, long-term follow-up studies are required to ascertain
whether donor limbal stem cell survival or promotion of recolonization
by resident recipient stem cells occurs in restored recipient
epithelium. However, this is not an easy task since a definitive
limbal stem cell marker has not been identified yet. This
review will discuss the therapeutic usage of limbal stem cells
in the corneal epithelial disorders.
[Back to top]
Non-HLA Gene Polymorphisms and the Outcome of Allogeneic
Hemato-poietic Stem Cell Transplantation
Katarzyna Bogunia-Kubik, Barbara Wysoczanska
and Andrzej Lange
Haematopoietic stem cell transplantation (HSCT) is a curative
treatment of many hematological disorders. However, although
significant advances have been made in donor-recipient matching
or conditioning regimens, HSCT is associated with a risk of
post transplant complications. Those include generation of
toxic lesions, graft-versus-host-disease (GvHD) and viral
reactivations. Recent studies have shown the association between
polymorphic features of non-HLA encoding genes and the incidence
and severity of post-transplant complications in the recipients
of allogeneic HSCT, implying that the donor-recipient genotyping,
extended for cytokine loci, may be of prognostic value for
the transplantation outcome. Thus, the pre-transplant analysis
of the patients’ genetic predisposition may be considered
as important factor allowing the classification of the transplant
recipients as less or more susceptible for developing toxic
lesions, severe and/or fatal acute GvHD or viral reactivation.
This review focuses on the relationship between the polymorphic
patterns of tumor necrosis factor (TNF)-α
and TNF-β,
IFN-γ ,
interleukin (IL)-6, IL-10 and heat shock protein (HSP)70-hom
encoding genes and the manifestation of post-transplant complications,
acute and chronic GvHD, generation of toxic lesions, viral
reactivations and mortality.
[Back to top]
Diabetes Mellitus: A Potential Target for Stem Cell
Therapy
Christopher J. Burns, Shanta J. Persaud and Peter M. Jones
Type 1 diabetes mellitus has received much attention
recently as a potential target for the emerging science of
stem cell medicine. In this autoimmune disease, the insulin-secreting
β-cells
of the pancreas are selectively and irreversibly destroyed
by autoimmune assault. Advances in islet transplantation procedures
now mean that patients with the disease can be cured by transplantation
of primary human islets of Langerhans. A major drawback in
this therapy is the availability of donor islets, and the
search for substitute transplant tissues has intensified in
the last few years. This review will describe the essential
requirements of a material designed as a replacement β-cell
and will look at the potential sources of such replacements.
These include embryonic stem (ES) cells and multipotent adult
stem/progenitor cells from a range of tissues including the
pancreas, intestine, liver, bone marrow and brain. These stem
cell populations will be evaluated and the different experimental
approaches that have been employed to derive functional insulin-expressing
cells will be discussed. The review will also look at the
capability of human ES (hES) cells generated by somatic cell
nuclear transfer and some adult stem cell populations such
as bone marrow-derived stem cells, to offer autologous transplant
material that would remove the need for immunosuppression.
In patients with Type 1 diabetes, auto-reactive T-cells are
programmed to recognise the insulin-producing β-cells.
As a result, for therapeutic replacement tissues, it may be
more sensible to derive cells that behave like β-cells
but are immunologically distinct. Thus, the potential of cells
derived from non-β-cell
origin to avoid the autoimmune response will also be discussed.
Finally, the review will summarise the future prospects for
stem cell therapies for diabetes and will highlight some of
the problems that may be faced by researchers working in this
area, such as malignancy, irreproducible differentiation strategies,
immune-system rejection and social and ethical concerns over
the use of hES cells
[Back to top]
Mechanisms of Neural Stem Cell Fate Determination:
Extracellular Cues and Intracellular Programs
Masahiko Abematsu, Ian Smith and Kinichi Nakashima
Multipotent neural stem cells (NSC) possess the ability
to self-renew and to generate the three major central nervous
system (CNS) cell types: neurons, astrocytes and oligodendrocytes.
However, the molecular mechanisms that control NSC fate specification
are not yet fully understood. Recent studies have provided
evidence that soluble protein mediators such as cytokines
and transcriptional factors play critical roles in cell fate
determination. Furthermore, it has become apparent that epigenetic
gene regulation plays an important intracellular role as cell-intrinsic
programs in the specification of cell lineages. In this review,
we focus on recent progress that addresses the mechanisms
of NSC fate specification and their possible contribution
in the field of regenerative medicine.
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