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Current
Stem Cell Research & Therapy
ISSN: 1574-888X
Current Stem
Cell Research & Therapy
Volume 1, Number 3, September 2006
Contents
Haematopoietic Stem Cell Gene Therapy to Treat Autoimmune
Disease Pp. 279-287
Frank Alderuccio, Christopher Siatskas, James
Chan, Judith Field, Kim Murphy, Zeyad Nasa and Ban-Hock Toh
[Abstract]
Oogenesis from Human Somatic Stem Cells and a
Role of Immune Adaptation in Premature Ovarian Failure
Pp. 289-303
Antonin Bukovsky
[Abstract]
Stem Cell Model of Hematopoiesis Pp.
305-315
Alice M.S. Cheung, Yok-Lam Kwong, Raymond Liang and Anskar
Y.H. Leung
[Abstract]
Advances in Umbilical Cord Blood Transplantation
Pp. 317-324
Karen K. Ballen
[Abstract]
Harnessing Pluripotency from Differentiated Cells:
A Regenerative Source for Tissue-Specific Stem Cell Therapies
Pp. 325-331
Ilham Saleh Abuljadayel
[Abstract]
Role of Growth Factors and Endothelial Cells in
Therapeutic Angiogenesis and Tissue Engineering Pp.
333-343
Masashi Nomi, Hideaki Miyake, Yoshifumi Sugita, Masato
Fujisawa and Shay Soker
[Abstract]
Adult Stem Cells in Bone and Cartilage Tissue
Engineering Pp. 345-364
António J. Salgado, João T. Oliveira, Adriano
J. Pedro and Rui L. Reis
[Abstract]
Adult Mesenchymal Stem Cells: A Pluripotent Population
with Multiple Applications Pp. 365-369
Christopher D. Porada, Esmail D. Zanjani and Graça
Almeida Porada
[Abstract]
Human Fetal Mesenchymal Stem Cells Pp.
371-386
Keelin O’Donoghue and Jerry Chan
[Abstract]
The Duality of Epidermal Growth Factor Receptor
(EGFR) Signaling and Neural Stem Cell Phenotype: Cell Enhancer
or Cell Transformer? Pp. 387-394
Angel Ayuso-Sacido, Christopher Graham, Jeff P. Greenfield
and John A. Boockvar
[Abstract]
Lessons from the Stem Cell Proteome Pp.
395-409
Bernd Gesslbauer, Evelyn Krenn, Christoph Zenzmaier, Karl
Heinz Preisegger, and Andreas J. Kungl
[Abstract]
Therapeutic Potential of Bone Marrow Stem Cells
for Liver Diseases Pp. 411-418
Felix C. Popp, Pompiliu Piso, Hans J. Schlitt and Marc
H. Dahlke
[Abstract]
What is the Best Option to Cure Patients with
Resistant/Relapsing Hodgkin’s Disease? Pp.
419-424
Massimo Magagnoli, Monica Balzarotti, Luca Castagna, Monica
Demarco and Armando Santoro
[Abstract]
Stem-Cell Therapy for Diabetes Cure: How Close
are We? Pp. 425-436
Anandwardhan A. Hardikar, Justin G. Lees, Kuldip S. Sidhu,
Emily Colvin and Bernard E. Tuch
[Abstract]
Abstracts
[Back to top]
Haematopoietic Stem Cell Gene Therapy to Treat Autoimmune
Disease
Frank Alderuccio, Christopher Siatskas, James
Chan, Judith Field, Kim Murphy, Zeyad Nasa and Ban-Hock Toh
Autoimmune diseases affect approximately 6% of the population
and are characterised by a pathogenic immune response that
targets self-antigens. Well known diseases of this nature
include type 1 diabetes, systemic lupus erythematosus, rheumatoid
arthritis and multiple sclerosis. Treatment is often restricted
to replacement therapy or immunosuppressive regimes and to
date there are no cures. The strategy of utilising autologous
or allogeneic haematopoietic stem cell transplantation to
treat autoimmunity and induce immunological tolerance has
been trailed with various levels of success. A major issue
is disease relapse as the autoimmune response is reinitiated.
Cells of the immune system originate from bone marrow and
have a central role in the induction of immunological tolerance.
The ability to isolate and genetically manipulate bone marrow
haematopoietic stem cells therefore makes these cells a suitable
vehicle for driving ectopic expression of defined autoantigens
and induction of immunological tolerance.
[Back to top]
Oogenesis from Human Somatic Stem Cells and a Role
of Immune Adaptation in Premature Ovarian Failure
Antonin Bukovsky
The central thesis is that, while embryonic oocytes originate
from extra-ovarian sources, those generated during fetal period
and in postnatal life are derived from the ovarian surface
epithelium (OSE). With the assistance of immune system-related
cells, primitive granulosa and germ cells appear to originate
from OSE stem cells in the fetal and adult human gonads. Fetal
primary follicles are formed during the second trimester of
intrauterine life, prior to the end of immune adaptation,
possibly in order to be recognized as self and renewed later.
With the onset of menarche, a periodical follicular renewal
emerges to replace aging primary follicles and ensure that
fresh eggs are always available during the prime reproductive
period. The periodical follicular renewal ceases between 35-40
years of age, and the remaining primary follicles are utilized
during the premenopausal period until exhausted. However,
the persisting oocytes accumulate genetic alterations and
may become unsuitable for ovulation and fertilization. Premature
ovarian failure (POF) may result from premature termination
of follicular renewal during adulthood, possibly due to the
alteration of fetal follicular development during immune adaptation
(idiopathic POF), or due to the alteration of the adult immune
system by cytostatic chemotherapy. Factors responsible for
the diminution of follicular renewal may be responsible for
the aging of other tissues and the whole body in general.
However, our recent research shows that OSE stem cells may
produce new eggs in vitro, even when derived from
ovaries lacking primary follicles. Consequently, their in
vitro fertilization (IVF) and subsequent utilization
of embryos for intrauterine implantation may represent a novel
IVF approach for providing genetically related children to
women with ovarian infertility, which is worthy of consideration
and further exploration.
[Back to top]
Stem Cell Model of Hematopoiesis
Alice M.S. Cheung, Yok-Lam Kwong, Raymond Liang and Anskar
Y.H. Leung
Hematopoietic stem cells (HSC) are characterized by their
capacity of self-renewal, multi-lineage differentiation, and
the ability to rescue lethally irradiated hosts. Both murine
and human studies have attempted to characterize and purify
HSC based on surface phenotypes, metabolic markers, in-vitro
clonogenic and in-vivo competitive repopulation assays.
The cell-fate of HSC is under intrinsic regulation by various
transcription factors, including Hox and SCL genes, cyclin-dependent
kinase inhibitors and telomerase, and extrinsic regulation
by various signaling pathways involved in embryonic development,
including the Notch, Wnt and bone morphogenetic proteins (BMP)
pathways. Recent advances in genome research and gene profiling
technologies have begun to unravel the regulatory mechanism
of HSC by novel genes with hitherto unknown functions in hematopoiesis.
The stem cell model of hematopoiesis has also shed light on
the concepts of leukemic stem cells (LSC), which involves
the presence of a rare population of cells that share the
essential HSC attributes of self-renewing, replication and
differentiation into progenies of leukemic blasts.
[Back to top]
Advances in Umbilical Cord Blood Transplantation
Karen K. Ballen
The first successful cord blood transplant was reported in
1989. In the last sixteen years, there has been a substantial
increase in the use of cord blood as an alternative stem cell
source for patients without matched related or unrelated bone
marrow donors. Approximately 5000 cord blood transplants have
been performed worldwide. Recently, the results in adult cord
blood transplantation appear promising. In this review, the
preclinical background, cord blood banking, and ethical issues
will be briefly addressed. Outcome data for both pediatric
and adult transplantation will be reviewed, with an emphasis
on new strategies for adult cord blood transplantation. New
indications for cord blood use outside of hematology/oncology
will also be explored.
[Back to top]
Harnessing Pluripotency from Differentiated Cells:
A Regenerative Source for Tissue-Specific Stem Cell Therapies
Ilham Saleh Abuljadayel
Processes involving conversion of mature adult cells into
undifferentiated cells have tremendous therapeutic potential
in treating a variety of malignant and non-malignant disorders,
including degenerative diseases. This can be achieved in autologous
or allogeneic settings, by replacing either defective cells
or regenerating those that are in deficit through reprogramming
more commited cells into stem cells. The concept behind reprogramming
differentiated cells to a stem cell state is to enable the
switching of development towards the required cell lineage
that is capable of correcting the underlying cellular dysfunction.
The techniques by which differentiated cells can reverse their
development, become pluripotent stem cells and transdifferentiate
to give rise to new tissue or an entire organism are currently
under intense investigation.
Examples of reprogramming differentiation in mature adult
cells include nuclear reprogramming of more commited cells
using the cytoplasm of empty oocytes obtained from a variety
of animal species, or cell surface contact of differentiated
cells through receptor ligand interaction. Such ligands include
monoclonal antibodies, cytokines or synthetic chemical compounds.
Despite controversies surrounding such techniques, the concept
behind identification and design/screening of biological or
pharmacological compounds to enable re-switching of cell fate
in-vivo or ex-vivo is paramount for current
drug therapies to be able to target more specifically cellular
dysfunction at the tissue/organ level. Herein, this review
discusses current research in cellular reprogramming and its
potential application in regenerative medicine.
[Back to top]
Role of Growth Factors and Endothelial Cells in Therapeutic
Angiogenesis and Tissue Engineering
Masashi Nomi, Hideaki Miyake, Yoshifumi Sugita, Masato
Fujisawa and Shay Soker
To achieve the goals of engineering large complex tissues,
and possibly internal organs, vascularization of the regenerating
tissue is essential. To maintain the initial volume after
implantation of regenerated tissue, improved vascularization
is considered to be important. Recent advances in understanding
the process of blood vessel growth has offered significant
tools for the neovascularization of bioengineered tissues
and therapeutic angiogenesis. Several angiogenic growth factors
including vascular endothelial growth factor (VEGF), basic
fibroblast growth factor (bFGF) and hepatocyte growth factor
(HGF) were used for vascularization of ischemic tissues. Other
approaches such as prevascularization of the scaffold, prior
to cell seeding, and incorporation of endothelial cells in
the bioengineered tissue showed encouraging results. In this
article, we will review recent advances in angiogenic growth
factors, and discuss the role of these growth factors and
endothelial cells in therapeutic angiogenesis and tissue engineering.
[Back to top]
Adult Stem Cells in Bone and Cartilage Tissue Engineering
António J. Salgado, João T. Oliveira, Adriano
J. Pedro and Rui L. Reis
The progressive increase in life expectancy within the last
century has led to the appearance of novel health related
problems, some of those within the musculoskeletal field.
Among the latter, one can find diseases such as osteoporosis,
rheumatoid arthritis and bone cancer, just to mention some
of the most relevant. Other related problems are those that
arise from serious injuries, often leading to non-recoverable
critical size defects. The therapies currently used to treat
this type of diseases/injuries are based on the use of pharmaceutical
agents, auto/allotransplant and synthetic materials. However,
such solutions present a number of inconveniences and therefore,
there is a constant search for novel therapeutic solutions.
The appearance of a novel field of science called Tissue engineering
brought some hope for the solution of the above mentioned
problems. In this field, it is believed that by combining
a 3D porous template – scaffold – with an adequate
cell population, with osteo or chondrogenic potential, it
will be possible to develop bone and cartilage tissue equivalents
that when implanted in vivo, could lead to the total
regeneration of the affected area. This ideal cell population
should have a series of properties, namely a high osteo and
chondrogenic potential and at the same time, should be easily
expandable and maintained in cultures for long periods of
time. Due to its natural and intrinsic properties, stem cells
are one of the best available cell types. However, after this
sentence, the readers may ask, “Which Stem Cells?”.
During the last 10/15 years, the scientific community witnessed
and reported the appearance of several sources of stem cells
with both osteo and chondrogenic potential. Therefore, the
present review intends to make an overview of data reported
on different sources of adult stem cells (bone marrow, periosteum,
adipose tissue, skeletal muscle and umbilical cord) for bone
and cartilage regenerative medicine, namely those focusing
on the differentiation potential of the latter as well as
in vivo proof of concept of their applicability.
Simultaneously novel aspects of adult stem cells biotechnology
such as their immunogenic characteristics and cell expansion
methodologies will also be put forward. The present review
also points out on issues such as the bone and cartilage regenerative
market, and gives a brief description on bone and cartilage
bone biology, so the readers can have a true idea of the current
state of the art, and how adult stem cells can be an added
value to this field.
[Back to top]
Adult Mesenchymal Stem Cells: A Pluripotent Population
with Multiple Applications
Christopher D. Porada, Esmail D. Zanjani and Graça
Almeida Porada
Mesenchymal stem cells (MSCs) have been isolated not only
from bone marrow, but also from many other tissues such as
adipose tissue, skeletal muscle, liver, brain and pancreas.
Because MSC were found to have the ability to differentiate
into cells of multiple organs and systems such as bone, fat,
cartilage, muscle, neurons, hepatocytes and insulin-producing
cells, MSCs have generated a great deal of interest for their
potential use in regenerative medicine and tissue engineering.
Furthermore, given the ease of their isolation and their extensive
expansion rate and differentiation potential, mesenchymal
stem cells are among the first stem cell types that have a
great potential to be introduced in the clinic. Finally, mesenchymal
stem cells seem to be not only hypoimmunogenic and thus be
suitable for allogeneic transplantation, but they are also
able to produce immunosuppression upon transplantation. In
this review we summarize the latest research in the use of
mesenchymal stem cells in transplantation for generalized
diseases, local implantation for local tissue defects, and
as a vehicle for genes in gene therapy protocols.
[Back to top]
Human Fetal Mesenchymal Stem Cells
Keelin O’Donoghue and Jerry Chan
Stem cells have been isolated at all stages of development
from the early developing embryo to the post-reproductive
adult organism. However, the fetal environment is unique as
it is the only time in ontogeny that there is migration of
stem cells in large numbers into different organ compartments.
While fetal neural and haemopoietic stem cells (HSC) have
been well characterised, only recently have mesenchymal stem
cells from the human fetus been isolated and evaluated. Our
group have characterised in human fetal blood, liver and bone
marrow a population of non-haemopoietic, non-endothelial cells
with an immunophenotype similar to adult bone marrow-derived
mesenchymal stem cells (MSC).
These cells, human fetal mesenchymal stem cells (hfMSC), are
true multipotent stem cells with greater self-renewal and
differentiation capacity than their adult counterparts. They
circulate in first trimester fetal blood and have been found
to traffic into the maternal circulation, engrafting in bone
marrow, where they remain microchimeric for decades after
pregnancy. Though fetal microchimerism has been implicated
in the pathogenesis of autoimmune disease, the biological
role of hfMSC microchimerism is unknown. Potential downstream
applications of hfMSC include their use as a target cell for
non-invasive pre-natal diagnosis from maternal blood, and
for fetal cellular and gene therapy. Using hfMSC in fetal
therapy offers the theoretical advantages of avoidance of
immune rejection, increased engraftment, and treatment before
disease pathology sets in. Aside from allogeneic hfMSC in
utero transplantation, the use of autologous hfMSC has
been brought a step forward with the development of early
blood sampling techniques, efficient viral transduction and
clonal expansion. Work is ongoing to determine hfMSC fate
post-transplantation in murine models of genetic disease.
In this review we will examine what is known about hfMSC biology,
as well as discussing areas for future research. The implications
of hfMSC trafficking in pregnancy will be explored and the
potential clinical applications of hfMSC in prenatal diagnosis
and fetal therapy discussed.
[Back to top]
The Duality of Epidermal Growth Factor Receptor (EGFR)
Signaling and Neural Stem Cell Phenotype: Cell Enhancer or
Cell Transformer?
Angel Ayuso-Sacido, Christopher Graham, Jeff P. Greenfield
and John A. Boockvar
Recruitment of neural stem cells (NSCs) represents an elegant
strategy for replacing adult central nervous system (CNS)
cells lost to injury or disease. However, except in the rostral
migratory stream to the olfactory bulb, the adult CNS harbors
a relatively non permissive environment for motility of neural
stem cells. This opens the possibility of therapeutic enhancement
of NSC motility towards sites of CNS injury or disease. The
Epidermal Growth Factor Receptor (EGFR) is involved in the
activation of a number of downstream pathways that regulate
the phenotype of progenitor cells. Activated EGFR tyrosine
kinase activity enhances NSC migration, proliferation, and
survival. However, EGFR signaling is also known to play a
role in the most malignant and highly invasive of human tumors,
glioblastoma multiforme (GBM). Recent evidence supports
the theory that GBM derives from a ‘cancer stem cell’
and that EGFR signals are commonly altered in these precursor
cells. This article will review the role of EGFR signaling
as it relates to neural stem cell motility and invasion. The
duality of altered EGFR signaling in neural progenitor cells
is discussed and opportunities for enhancing the recruitment
of adult progenitors, and consequences of altering EGFR signaling
in progenitor cells will be highlighted.
[Back to top]
Lessons from the Stem Cell Proteome
Bernd Gesslbauer, Evelyn Krenn, Christoph Zenzmaier, Karl
Heinz Preisegger, and Andreas J. Kungl
The proteome of a cell is a molecular fingerprint directly
relating to the gene expression snapshot profile at a certain
point of time or developmental stage. Monitoring the expansion
and the differentiation state of stem cells by proteomic means
seems therefore a very attractive method for diagnostic as
well as for therapeutic purposes. We have investigated the
protein expression patterns of umbilical cord blood-derived
CD34+/AC133+ cells in order to obtain a most comprehensive
view of the stem cell proteome. For this purpose, we have
applied 2-D gel electrophoresis and 2-D chromatography for
most efficient protein/peptide separation and characterisation.
The proteins were identified after tryptic digestion by nano-HPLC
coupled directly to an ion trap mass spectrometer. An extensive
bioinformatic analysis of the protein obtained revealed a
dynamic stem cell proteome. This means that the heterogeneity
of protein expression patterns obtained from different stem
cell preparations refers to a limited set of stem cell-specific
house keeping proteins as well as to a large number of proteins
which depend on (marginal) stimuli from the environment. Since
those are difficult to standardise, snapshot views of the
stem cell proteome reflect not only stem cell-intrinsic metabolism
but also the strong influence of the sample history on protein
expression patterns.
[Back to top]
Therapeutic Potential of Bone Marrow Stem Cells for
Liver Diseases
Felix C. Popp, Pompiliu Piso, Hans J. Schlitt and Marc
H. Dahlke
Stem cells of the bone marrow, including hematopoietic
stem cells (HSC), mesenchymal stem cells (MSC) and hepatic
progenitors were reported to give rise to hepatocytes by both
transdifferentiation and cellular fusion. Transdifferentiation
was observed without liver damage although significant numbers
of stem cell derived hepatocytes were not described. Cellular
fusion was demonstrated in the presence of a proliferation
stimulus in conjunction with impaired intrinsic liver regeneration
capacity.
Here, we review potential therapeutic applications of stem
cell derived hepatocytes depending on how they emerge. Stem
cells turning into hepatocytes by transdifferentiation introduce
new functioning liver cells into a diseased organ, which can
support intrinsic liver regeneration or bridge the time gap
until a definitive treatment is available. When cellular fusion
is the mechanism behind stem cell plasticity, however, no
new cells emerge in the first place, whereas new genetic material
is introduced. The fusion cell thereby acquires a selective
advantage over resident hepatocytes allowing for extensive
proliferation and liver repopulation. Therefore genetic deficiencies
might be the predominant target for cell fusion therapies.
We conclude that transdifferentiation and cellular fusion
might be powerful tools for the therapy of liver diseases
in the future and we propose the introduction of artificial
cell fusion as well as stem cell differentiation as therapeutic
options.
[Back to top]
What is the Best Option to Cure Patients
with Resistant/Relapsing Hodgkin’s Disease?
Massimo Magagnoli, Monica Balzarotti, Luca Castagna, Monica
Demarco and Armando Santoro
Nearly 80% of patients with Hodgkin's disease (HD) are cured
with chemotherapy with or without radiotherapy. However, in
patients with primary refractory or relapsed disease, high-dose
therapy (HDT) and autologous or peripheral-blood stem-cell
transplantation (ASCT or PBSCT) represents the best curative
option. Several prognostic factors to identify patients at
high risk for relapse or progression have been analyzed. However,
in almost all analyzed series, disease status before high-dose
chemotherapy with PBSC support remains the most important
factor predicting the outcome of these patients. Nonetheless,
the benefit of cytoreduction before HDT has yet to be fully
determined and efforts to identify the best active regimen,
combining therapeutic activity and CD34+ stem-cell mobilizing
potential, represent a challenging issue for these patients.
Furthermore new approaches like myeloablative and non-myeloablative
allogeneic transplants have been assessed to improve long-term
in such patients. In this review we analyzed the results of
the most important salvage chemotherapy combinations as well
as allogeneic transplantations to clarify the optimal treatment
options for patients with resistant/relapsing HD.
[Back to top]
Stem-Cell Therapy for Diabetes Cure: How Close are
We?
Anandwardhan A. Hardikar, Justin G. Lees, Kuldip S. Sidhu,
Emily Colvin and Bernard E. Tuch
Transplantation of insulin-producing cells offers a promising
therapy to treat diabetes. However, due to the limited number
of donor islet cells available, researchers are looking for
different sources of pancreatic islet progenitor or stem cells.
A stem cell with extensive proliferative ability may provide
a valuable source of islet progenitor cells. Several studies
have demonstrated that a progenitor/stem-cell population can
be expanded in vitro to generate large numbers of
islet progenitor cells. However, efficient and directed differentiation
of these cells to an endocrine pancreatic lineage has been
difficult to achieve. We discuss here various pancreatic islet
stem cells that we and others have obtained from embryonic,
fetal or adult human tissues. We review the progress that
has been achieved with pancreatic islet progenitor cell differentiation
in the last 2 decades and discuss how close we are to translate
this research to the clinics.
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