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Current
Stem Cell Research & Therapy
ISSN: 1574-888X
Current Stem
Cell Research & Therapy
Volume 1, Number 1, January 2006
Content
Application of stem cells in cardiology: Where we are and
where we are going Pp. 1-11
José Marín-García and Michael J.
Goldenthal
[Abstract] [Full
Text Article]
The Importance of Adipose-Derived Stem Cells and
Vascularized Tissue Regeneration in the Field of Tissue Transplantation
Pp. 13-20
Rei Ogawa
[Abstract] [Full
Text Article]
Mesenchymal stem cell-based HLA-independent cell
therapy for tissue engineering of bone and cartilage
Pp. 21-27
Philipp Niemeyer, Ulf Krause, Philip Kasten, Peter C.
Kreuz,Philipp Henle, Norbert P. Südkamp, Alexander Mehlhorn
[Abstract] [Full
Text Article]
Dose-intensive chemotherapy with stem cell support
as a treatment strategy for bone and soft-tissue sarcomas
Pp. 29-35
Bernd Kasper, Anthony D. Ho, Gerlinde Egerer
[Abstract] [Full
Text Article]
Respiratory stem cells and progenitors: overview,
derivation, differentiation, carcinogenesis, regeneration,
and therapeutic application Pp. 37-46
Shibichakravarthy Kannan and Min Wu
[Abstract] [Full
Text Article]
Cryopreserving Human Peripheral Blood Progenitor
Cells Pp. 47-54
Anne Margrethe Bakken
[Abstract] [Full
Text Article]
Understanding stem cell-mediated brain repair
through neuroimaging Pp. 55-63
Mike Modo
[Abstract] [Full
Text Article]
Screening the brain: molecular fingerprints of
neural stem cells Pp. 65-77
Martin H. Maurer and Wolfgang Kuschinsky
[Abstract] [Full
Text Article]
Neural Stem Cells - A Promising Potential Therapy
for Brain Tumors Pp. 79-84
Irvin, Dwain; Yuan, Xiangpeng; Tunici, Patricia Yu, John
S.
[Abstract] [Full
Text Article]
Our Perception of Developmental Plasticity
Esse Est Percipi (to be is to be Perceived)? Pp.
85-94
Nadir Askenasy, Isaac Yaniv, Jerry Stein, Saul J. Sharkis
[Abstract] [Full
Text Article]
The stem state: Mesenchymal plasticity as a paradigm
Pp. 95-102
Dov Zipori
[Abstract] [Full
Text Article]
Intracellular Signaling Pathways Regulating Pluripotency
of Embryonic Stem Cells Pp. 103-111
Keisuke Okita and Shinya Yamanaka
[Abstract] [Full
Text Article]
Epithelial Stem Cells and Tissue Engineered Intestine
Pp. 113-120
Richard M. Day
[Abstract] [Full
Text Article]
Dendritic cell therapy for tolerance induction
during stem cell transplantation Pp. 121-125
Helen C. O’Neill
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Application of stem cells in cardiology: Where we are and
where we are going
José Marín-García and Michael
J. Goldenthal
[Full Text Article]
Heart disease including myocardial infarction and ischemia
is associated with the irreversible loss of cardiomyocytes
and vasculature, both via apoptosis or necrosis.
However, the native capacity for the renewal and repair of
myocardial tissue is inadequate as have been current therapeutic
measures to prevent left ventricular remodeling. Cell transplantation
has emerged as a potentially viable therapeutic approach to
directly repopulate and repair the damaged myocardium. A detailed
analysis and a vision for future progress in stem cell applications,
both in research and clinical cardiology is presented in this
review, highlighting the use of a wide spectrum of stem/progenitor
cell types including embryonic or fetal stem cells, myoblasts,
and adult bone marrow stem cells. An up-to-date comparison
of donor cell-types used, and evaluation of the myocardial
disorders that might be most amenable to stem cell therapy
are discussed. The roles that myocardial cell fusion and transdifferentiation
play in stem cell transplantation, the specific shortcomings
of available technologies, and recommendations for practical
ways that these concerns might be overcome are also presented.
[Back to top]
The Importance of Adipose-Derived Stem Cells and Vascularized
Tissue Regeneration in the Field of Tissue Transplantation
Rei Ogawa
[Full Text Article]
The importance of stem cells in regenerating or repairing
damaged or diseased tissues is well established, but three
factors have to be considered in employing stem cells clinically.
The first is how to harvest, handle, and multiply them non-invasively,
easily, and effectively. From this standpoint, adipose-derived
stem cells are considered to be the best to work with among
mesenchymal stem cells; since they were first reported in
2001, their pluripotency, proliferative efficiency, and low
donor morbidity have been amply confirmed. The second factor
is how to differentiate stem cells into the required cells
and use them effectively to construct three-dimensional tissues;
here, tissue-specific scaffolds and signaling systems are
essential. The third factor is how to ensure survival of the
differentiated cells and regenerated tissues. Regenerated
tissues need to contain vascular systems to allow both the
tissues themselves and the differentiated cells to survive.
Thus, we believe that the vascularization of regenerated tissues
will be an important field of research in the near future.
In this paper, we focus on adipose-derived stem cells and
vascularized tissue regeneration within the context of tissue
transplantation.
[Back to top]
Mesenchymal stem cell-based HLA-independent cell therapy
for tissue engineering of bone and cartilage
Philipp Niemeyer, Ulf Krause, Philip Kasten, Peter
C. Kreuz,Philipp Henle, Norbert P. Südkamp, Alexander
Mehlhorn
[Full Text Article]
Mesenchymal stem cells (MSC) can be obtained from human
bone marrow aspirates and, thanks to their differentiation
potential and excellent in vitro culture properties,
represent an attractive cell line for the regeneration of
mesenchymal tissue. Both in vitro and in vivo,
they can differentiate into cartilage, bone, tendons and fat
cells, and—in contrast to embryonic stem cells—they
are not under ethical scrutiny. Cultured on three-dimensional
scaffolds according to the tissue engineering concept, they
have already been successfully employed for reconstruction
of mesenchymal tissues in numerous studies involving both
small and large animal models. Recently, immunological properties
of hMSC have been investigated by several groups. On the basis
of the available literature, hMSC have to be referred to as
immune privileged, and they seem to be available for HLA-independent
cell transplantation. While clinical MSC transplantation has
also been successfully performed in pilot studies in humans,
numerous points still remain to be clarified, underscoring
the need for further intensive research before large-scale
clinical application can be contemplated. Only then can it
be shown whether the associated high expectations are justified.
[Back to top]
Dose-intensive chemotherapy with stem cell support as a
treatment strategy for bone and soft-tissue sarcomas
Bernd Kasper, Anthony D. Ho, Gerlinde Egerer
[Full Text Article]
Whether high-dose chemotherapy with stem cell support improves
the long-term outcome for patients with bone and soft-tissue
sarcoma is debatable and controversial. Prognosis of patients
with unresectable or advanced metastatic sarcoma remains poor
with a disease-free survival at 5 years less than 10%; treatment
is generally considered to be palliative. Doxorubicin, epirubicin
and ifosfamide are the most active single agents with response
rates above 20%. Although drug combinations result in higher
response rates, superiority against single agent chemotherapy
in terms of survival could not have been demonstrated yet.
As a dose-response relationship has been shown for the anthracyclines
and especially for ifosfamide, high-dose chemotherapy with
stem cell support has been evaluated by several investigators.
However, all studies were not randomized, comprised small
patient numbers and included heterogeneous histological subtypes
of soft-tissue sarcomas. Nevertheless, higher doses of chemotherapy
result in higher remission rates, which could correlate with
longer survival. Well-designed randomized trials should be
performed.
[Back to top]
Respiratory stem cells and progenitors: overview, derivation,
differentiation, carcinogenesis, regeneration, and therapeutic
application
Shibichakravarthy Kannan and Min Wu
[Full Text Article]
Recently, research of stem cells has garnered great attention
and has shown promise by changing the view of traditional
therapeutics, with broad impact on gene therapy, carcinogenesis,
organ development, tissue injury, regeneration and almost
all aspects of the life cycle and all living systems. A century’s
scientific progress has significantly improved controls for
infectious diseases and many other disorders. However, many
remaining problems (i.e. cancer, AIDS, diabetes, Parkinson’s
disease and Marburg infection) appear to be even harder than
those that have already been solved. In particular, respiratory
stem cell research has been less active and has moved more
slowly than that of many other organs. This is probably due
to the complexity of the lung and airway system, particularly
owing to the many types of cells (>40), unique structures
and functions, and technical difficulty in analyzing this
system at the genetic, biochemical, molecular and cellular
level. Compared with other epithelial cells (i.e., gastrointestinal
epithelium), respiratory epithelia have a very low turnover
rate and minimal regenerative activity. This review will discuss
the current state of pulmonary stem cells, their origin, development,
differentiation, and regenerative application, with a particular
focus on potential impact on cancer development and lung injury
repair.
[Back to top]
Cryopreserving Human Peripheral Blood Progenitor Cells
Anne Margrethe Bakken
[Full Text Article]
High-dose chemotherapy followed by autologous peripheral
blood progenitor cell (PBPC) transplantation is used in the
treatment of chemosensitive malignancies. Cryopreservation
of PBPC in 10% dimethyl sulfoxide (DMSO) has been the standard
procedure in most institutions. Infusion of PBPC cryopreserved
with DMSO can be associated with toxic reactions such as vomiting,
cardiac dysfunction, anaphylaxia and acute renal failure.
The grade of toxicity experienced by patients is related to
the amount of DMSO present in the PBPC. Cryopreservation with
lower DMSO concentrations would be expected to reduce the
toxicity. In recent studies done with PBPC cells cryopreserved
with 5%, 4% and 2% DMSO, using 10% DMSO as a reference control,
CD34+ cells were investigated for preservation
of viability, apoptosis, and necrosis. Also preservation of
mature colony-forming (CFU) cells, specifically mature myeloid,
erythroid progenitors, CFU-megakaryocytes and long-term culture-initiating
cells (LTC-ICs) were investigated, using 5% and 10% DMSO as
cryoprotectant. All samples were frozen in a rate-controlled
programmed freezer and stored in the vapor phase of liquid
nitrogen until used. Conclusion: 5% DMSO is the optimal concentration
for cryopreserving human PBPC in vitro. Consequently,
some hospitals have started using 5% DMSO as cryoprotectant
for the autologous PBPC as a standard procedure.
[Back to top]
Understanding stem cell-mediated brain repair through neuroimaging.
Mike Modo
[Full Text Article]
Transplantation of stem cells into the damaged brain can
lead to behavioral recovery. However, at present the mechanisms
by which these cells exert their beneficial effects are still
poorly understood. Survival, migration and differentiation
are but a few of the factors that are thought to be involved
in stem cell-mediated brain repair. It is hoped that neuroimaging,
by MRI and PET, will provide serial in vivo assessments
of transplanted cells that can lead to a greater understanding
of the mechanisms involved in brain repair.
[Back to top]
Screening the brain: molecular fingerprints of neural stem
cells
Martin H. Maurer, Wolfgang Kuschinsky
[Full Text Article]
With the development of high-throughput technologies like
microarrays for genomic and transcriptomic analysis, and two-dimensional
gel electrophoresis, mass spectrometry, and protein arrays
for proteomic analysis, it is possible to monitor the changes
in gene or protein expression of several hundreds, or even
thousands of molecules simultaneously. Within the last years,
these technologies have been applied successfully to stem
cell research. One of the aims of stem cell expression profiling
is to find specific marker genes or proteins which may determine
the "stemness" of these cells. In the current review,
we will evaluate the results of genomic, transcriptomic and
proteomic approaches to find stem cell markers.
We compare the criteria of "stemness" to recent
results in adult neural stem cell research. Neural stem cells
have been isolated from various regions of the adult brain.
They self-renew and give rise to progeny capable to generate
neurons, astrocytes, and oligodendrocytes. Besides morphological
differentiation, these cells can integrate into functional
neuronal circuits, making them suitable targets for cell replacement
strategies. General properties seem to be the responsiveness
to growth factors, and the activation of developmental signaling
pathways. In conclusion, we suggest that stem cell properties
can be specified by global gene or proteomic expression patterns
rather than by the analysis of individual genes or proteins.
[Back to top]
Neural Stem Cells - A Promising Potential Therapy for Brain
Tumors
Irvin, Dwain; Yuan, Xiangpeng; Tunici, Patricia; Yu,
John S.
[Full Text Article]
Brain tumors can be highly aggressive and debilitating for
many patients and lead to an untimely death in just a few
months. Unfortunately, due to the location of many brain tumors,
therapy with ionizing radiation, chemotherapeutic agents and/or
surgery has limited rewards. In addition, the probability
of totally removing highly infiltrative tumors, particularly
gliomas, is extremely low. Currently, these methods rarely
provide a cure for many patients. The need for directed targeting
and ablation of tumors with minimal damage to nearby healthy
tissue has lead to the most recent findings and uses of neural
stem cells for therapeutic treatment of brain tumors. Recently,
some very promising studies have demonstrated that exogenous
neural stem cells have the remarkable ability to migrate very
long distances towards sites of metastasis after transplantation.
These studies also show that intravascular injections of neural
stem cells may lead to preferential migration towards central
nervous system tumors. It has also been demonstrated that
genetically modified neural stem cells, engineered to produce
anti-tumor molecules, upon transplantation, have the ability
to migrate towards tumors and reduce tumor mass directly or
through a “bystander” effect. Here we review the
current literature examining the promise of utilizing genetically
modified neural stem cells as vehicles for CNS tumor therapy.
[Back to top]
Our Perception of Developmental Plasticity
Esse Est Percipi (to be is to be Perceived)?
Nadir Askenasy, Isaac Yaniv, Jerry Stein, Saul
J. Sharkis
[Full Text Article]
The continuing interest in the biology of stem cells is
enhanced by new discoveries surrounding developmental plasticity
of both embryonic and adult stem cells. Adoptive transfer
of concepts and definitions from the hematopoietic system
for the existence of other tissue stem cells suggests inclusion
of characteristics such as ability to self-renew and differentiate
to functionally reconstitute a tissue/organ of origin. How
adequate and accurate are these definitions? Within the great
unknown of how these cells function, modulate their gene expression
patterns and respond to extrinsic signals, it is apparent
that there are numerous levels of stemness. We may envision
a scale of developmental flexibility. At one end of the scale
are positioned the embryonic stem cells, and at the other
end are positioned partially-differentiated, differentiation
restricted (committed) tissue/organ stem cells. There is evidence
that some stem cells in the adult are pluripotent, thus positioned
close to the embryonic end of the stem scale. It is uncertain
yet to what extent stem cells can move back and forth along
the stem scale.
[Back to top]
The stem state: Mesenchymal plasticity as a paradigm
Dov Zipori
[Full Text Article]
The mesenchyme is a remarkably plastic tissue in the embryo.
Recent studies led to the discovery of mesenchymal cells in
the adult organism that can differentiate in vitro
into unexpected directions, beyond the well known ability
of the mesenchyme to give rise to mesodermal derivatives.
These studies highlighted the plastic nature of the mesenchyme,
also beyond the embryonic developmental stage. This review
discusses the possible functions of the mesenchyme in the
adult and the reason for the maintenance of plasticity throughout
mammalian life. The properties of the mesenchymal cells clearly
exemplify the stem state concept; cells whether early or late
in the differentiation cascade may assume a stem state that
entails high plasticity.
[Back to top]
Intracellular Signaling Pathways Regulating Pluripotency
of Embryonic Stem Cells
Keisuke Okita and Shinya Yamanaka
[Full Text Article]
The cytokine LIF and its downstream effector STAT3 are essential
for maintenance of pluripotency in mouse ES cells. The requirement
for the transcription factor Oct3/4 for ES cell pluripotency
is also well-documented. However, LIF is not involved in self-renewal
of human ES cells, suggesting that other pathways must play
an important role in this process. The importance of other
signal transduction pathways, including BMP and Wnt signalings,
as well as novel transcription factors such as Nanog, is now
being recognized. We will review the rapid progress that has
been made in identifying and dissecting the intracellular
signaling pathways that contribute to self-renewal of pluripotent
mouse and human ES cells.
[Back to top]
Epithelial Stem Cells and Tissue Engineered Intestine
Richard M. Day
[Full Text Article]
The intestinal mucosa has an amazing regenerative capacity,
enabling rapid restoration of its physiological functions
following injury. The ability to do this resides with the
epithelial stem cells located within glandular invaginations
in the mucosal surface. Recent advances in the isolation and
characterization of epithelial stem cells has paved the way
for exploring novel therapeutic approaches for gastrointestinal
disease. Possible stem cell-based therapy of gastrointestinal
disorders range from the repair of damaged mucosa through
to tissue engineering of artificial intestinal constructs
for patients with short bowel syndrome. Before these benefits
are realized further information is required on the biological
characteristics of intestinal stem cells, their interactions
with surrounding cells, and the environment in which they
reside. This includes discovering markers to assist in the
identification and purification of stem cell populations and
techniques to manipulate the cells both in vivo and
in vitro. Because intestinal transplantation for patients
still represents a significant challenge, it is hoped that
one day a tissue-engineered intestine will provide a feasible
option for patients with short bowel syndrome. This review
aims to introduce the reader to the main characteristics of
epithelial stem cells and provide an overview of the current
status of intestinal tissue engineering and the problems still
being faced.
[Back to top]
Dendritic cell therapy for tolerance induction during stem
cell transplantation
Helen C. O’Neill
[Full Text Article]
With rapid progress in identification of a variety of adult
stem cells, there is an urgent need for basic studies on immunomodulatory
protocols relevant to stem cell transplantation. There are
now new possibilities for immunomodulation invoking the function
of DC in the induction of tolerance. This paper addresses
the application of DC immunotherapy for establishing and maintaining
peripheral tolerance to stem cell or tissue allografts. While
recent approaches target immature DC and their role in peripheral
tolerance, many questions can be raised about the tolerogenic
properties of those cells and the clinical feasibility of
their use. Procedures published to date for preparation of
DC differ significantly in terms of the source of cells and
methods for culture and expansion of immature, apparently
tolerogenic DC. With evidence for tolerogenicity associated
with all classes or lineages of DC, the hypothesis is advanced
that the tolerogenicity of DC is determined during hematopoiesis
and may be best established by immunotherapy using DC progenitors.
It is expected that peripheral tolerance and central or thymic-based
tolerance may complement each other as two essential mechanisms
for transplantation tolerance since different clinical situations
may invoke the need for different procedures for tolerance
induction.
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