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Current
Stem Cell Research & Therapy
ISSN: 1574-888X
Current Stem
Cell Research & Therapy
Volume 2, Number 3, September 2007
Contents
Is There a Clinical Future for Spermatogonial Stem Cells?
Pp. 189-195
Goossens Ellen and Tournaye Herman
[Abstract]
Deriving Respiratory Cell Types from Stem Cells
Pp. 197-208
Fredrik Olsson, Mark Denham, Timothy J. Cole, Stuart B.
Hooper and Richard Mollard
[Abstract]
The Response of Human Mesenchymal Stem Cells to Osteogenic
Signals and its Impact on Bone Tissue Engineering
Pp. 209-220
Ramakrishnaiah Siddappa, Hugo Fernandes, Jun Liu, Clemens
van Blitterswijk and Jan de Boer
[Abstract]
CD34+ Fibrocytes:
Morphology, Histogenesis and Function Pp. 221-227
Peter J. Barth and Christina C. Westhoff
[Abstract]
Potential for Clinical Ex Vivo Expansion
of Cord Blood Haemopoietic Stem Cells Using Non-Haemopoietic
Factor Supplements Pp. 229-237
Jonathon F. Hutton, Richard J. D’Andrea and Ian
D. Lewis
[Abstract]
Use of Radioimmunotherapy in Stem Cell Transplantation
and Posttransplantation: Focus on Yttrium
90 Ibritumomab Tiuxetan Pp. 239-248
Arturo Molina, Amrita Krishnan, Henry Fung, Ian W. Flinn,
David Inwards, Jane N. Winter and Auayporn Nademanee
[Abstract]
Imatinib Mesylate in Chronic Myeloid Leukemia
Pp. 249-251
Angelo Michele Carella and Enrica Lerma
[Abstract]
Stem Cell Defects in Philadelphia Chromosome Negative
Chronic Myeloproliferative Disorders: A Phenotypic and Molecular
Puzzle? Pp. 253-263
Oliver Bock, Kais Hussein and Hans Kreipe
[Abstract]
Abstracts
[Back to top]
Is There a Clinical Future for Spermatogonial Stem Cells?
Goossens Ellen and Tournaye Herman
Like every other adult stem cell in the human body, spermatogonial
stem cells (SSCs) have the capacity to either renew themselves
or to start the differentiation process, namely, spermatogenesis.
Due to the continuation of the stem cell population in the
testis, several possible options for preservation and re-establishment
of the reproductive potential exist. Currently, spermatogonial
stem cell transplantation (SSCT) is considered the most promising
tool for fertility restoration in young cancer patients. This
technique involves the injection of a testicular cell suspension
from a fertile donor into the testis of an infertile recipient.
Although, SSCT could prove important for fertility preservation,
this technique is not without any risk. Testicular cell suspensions
from cancer patients may be contaminated with cancerous cells.
It is obvious that reintroduction of malignant cells into
an otherwise cured patient must be omitted. Decontamination
strategies to solve this problem are discussed. Another alternative
to preserve male fertility could be in-vitro culture
of SSCs. This approach may be applied to generate spermatozoa
in-vitro from cultured spermatogonial stem cells,
which, in turn, could be used for intracytoplasmic sperm injection.
Xenogeneic transplantation and xenografting are two other
hypothetical methods to preserve fertility. However, because
of the ethical and biological concerns inherent to these approaches,
xenogeneic transplantation and xenografting should be limited
to research. When SSCT or SSC culture becomes available for
clinical use, efficient protocols for the cryopreservation
of SSCs and testicular tissue will be of great benefit. The
search for an optimal freezing protocol is discussed. Apart
from fertility preservation, SSC studies are useful for other
applications as well, such as transgenerational gene therapy
and cell-based organ regeneration therapy.
[Back to top]
Deriving Respiratory Cell Types from Stem Cells
Fredrik Olsson, Mark Denham, Timothy J. Cole, Stuart B.
Hooper and Richard Mollard
The reported pluripotential capabilities of many human stem
cell types has made them an attractive area of research, given
the belief they may hold considerable therapeutic potential
for treating a wide range of human diseases and injuries.
Although the bulk of stem cell based research has focused
on developing procedures for the treatment of pancreatic,
neural, cardiovascular and haematopoietic diseases, the potential
for deriving respiratory cell types from stem cells for treatment
of respiratory specific diseases has also been explored. It
is suggested that stem cell derivatives may be used for lung
replacement/regeneration therapeutics and high though-put
pharmacological screening strategies for a variety of respiratory
injuries and diseases including: cystic fibrosis, chronic
obstructive pulmonary disease, respiratory distress syndrome,
pulmonary fibrosis and pulmonary edema. This review will explore
recent progress in characterizing adult respiratory and bone
marrow derived stem cells with respiratory potential as well
as the endogenous mechanisms directing the homing of these
cells to the diseased and injured lung. In addition, the potential
for embryonic stem cell based therapies in this domain as
well as the histological, anatomical and molecular aspects
of respiratory development will be summarized.
[Back to top]
The Response of Human Mesenchymal Stem Cells to Osteogenic
Signals and its Impact on Bone Tissue Engineering
Ramakrishnaiah Siddappa, Hugo Fernandes, Jun Liu, Clemens
van Blitterswijk and Jan de Boer
Bone tissue engineering using human mesenchymal stem cells
(hMSCs) is a multidisciplinary field that aims to treat patients
with trauma, spinal fusion and large bone defects. Cell-based
bone tissue engineering encompasses the isolation of multipotent
hMSCs from the bone marrow of the patient, in vitro
expansion and seeding onto porous scaffold materials. In
vitro pre-differentiation of hMSCs into the osteogenic
lineage augments their in vivo bone forming capacity.
Differentiation of hMSCs into bone forming osteoblasts is
a multi-step process regulated by various molecular signaling
pathways, which warrants a thorough understanding of these
signaling cues for the efficient use of hMSCs in bone tissue
engineering. Recently, there has been a surge of knowledge
on the molecular cues regulating osteogenic differentiation
but extrapolation to hMSC differentiation is not guaranteed,
because of species- and cell-type specificity. In this review,
we describe a number of key osteogenic signaling pathways,
which directly or indirectly regulate osteogenic differentiation
of hMSCs. We will discuss how and to what extent the process
is different from that in other cell types with special emphasis
on applications in bone tissue engineering.
[Back to top]
CD34+ Fibrocytes:
Morphology, Histogenesis and Function
Peter J. Barth and Christina C. Westhoff
The connective tissue of virtually all human organs harbors
huge amounts of resident CD34+
fibrocytes. Recent studies have shown that CD34+
fibrocytes derive from circulating CD14+
monocytes. CD34+
fibrocytes are involved in wound healing, act as antigen presenting
cells and secrete a multitude of cytokines. Due to their diverse
functions CD34+
fibrocytes play a role in connective tissue diseases, pulmonary
fibrosis and tumor associated stromal remodeling. Stromal
remodeling precipitated by invasive carcinomas is characterized
by a loss of CD34+
expression paralleled by a gain of α-SMA
expression in stromal cells resulting in a phenotype change
from CD34+
fibrocytes towards α-SMA
positive myofibroblasts. This process is very stereotypic
and may play an essential role in local tumor invasion and
systemic dissemination, since a reduction of antigen presenting
CD34+ fibrocytes
might constitute a step in escaping the hosts´ immune
control directed against invasive carcinoma cells.
[Back to top]
Potential for Clinical Ex Vivo Expansion
of Cord Blood Haemopoietic Stem Cells Using Non-Haemopoietic
Factor Supplements
Jonathon F. Hutton, Richard J. D’Andrea and Ian
D. Lewis
The establishment of culture systems that promote haemopoietic
stem cell (HSC) self-renewal and expansion ex vivo
will increase the clinical potential of umbilical cord blood
(CB) HSC transplantation. Studies defining key signalling
pathways that regulate development and expansion of HSC in
vivo have greatly facilitated development of protocols
for expanding HSC in ex vivo culture. Recently a
number of soluble factors with novel stem cell expansion activity
have been identified as part of pathways associated with mesodermal
induction, or as factors produced by supportive stroma. These
have been reported to support, to varying degrees, HSC self-renewal
under in vitro conditions. Here we review the activities
of these new factors and consider their future potential as
components in ex vivo expansion culture for CB HSC.
Finally we discuss the challenges associated with applying
these factors to clinically relevant culture systems.
[Back to top]
Use of Radioimmunotherapy in Stem Cell Transplantation
and Posttransplantation: Focus on Yttrium
90 Ibritumomab Tiuxetan
Arturo Molina, Amrita Krishnan, Henry Fung, Ian W. Flinn,
David Inwards, Jane N. Winter and Auayporn Nademanee
Although autologous stem cell transplantation (ASCT) produces
prolonged disease-free survival in many patients with non-Hodgkin’s
lymphoma (NHL), relapse remains the most common cause of treatment
failure. Because of the potential benefit of adding targeted
irradiation to conditioning regimens, clinical trials are
testing the safety and efficacy of combining radioimmunotherapy
with yttrium 90 ibritumomab tiuxetan or iodine 131 tositumomab
and chemotherapy, either as replacement for total body irradiation
or in addition to standard high-dose chemotherapy (HDC) regimens.
Current strategies include using standard or escalated doses
of radioimmunoconjugates with HDC before ASCT in patients
with relapsed or refractory B-cell NHL. We reviewed the safety
and efficacy of 90Y ibritumomab
tiuxetan as part of the conditioning regimen before ASCT.
Preliminary data from phase 1 and 2 trials show that 90Y
ibritumomab tiuxetan may be safely added to HDC preparative
regimens for high-risk B-cell NHL. Additionally, comparisons
of outcomes with radioimmunotherapy and ASCT with historical
controls suggest that it may be more effective than conventional
regimens. Results of 90Y
ibritumomab tiuxetan alone posttransplantation in select patients
who have relapsed after HDC and ASCT are also encouraging.
Studies of 90Y ibritumomab
tiuxetan in the setting of allogeneic stem cell transplantation
appear promising as well.
[Back to top]
Imatinib Mesylate in Chronic Myeloid Leukemia
Angelo Michele Carella and Enrica Lerma
Chronic myeloid leukemia has become a paradigm for the discovery
of target therapeutic approaches in the field of onco-hematology.
Recognition of the tyrosine kinase activity of the p210Bcr-Abl
oncoprotein led to the development of compounds targeting
against BCR-ABL and then controlling the leukemic proliferation.
Imatinib mesylate, one of the first tyrosine kinase inhibitors
developed, was found effective and safe. According to five-years
experience with this drug, it is recommended that the golden
standard for initial treatment of newly diagnosis chronic
myeloid leukemia patients should be 400 mg Imatinib daily.
In this brief review, we discuss the current tools for the
effective management of chronic myeloid leukemia with Imatinib,
providing the updated results of IRIS and RIGHT clinical trials
and then the suggestions how Imatinib-treated patients should
be monitored.
[Back to top]
Stem Cell Defects in Philadelphia Chromosome Negative
Chronic Myeloproliferative Disorders: A Phenotypic and Molecular
Puzzle?
Oliver Bock, Kais Hussein and Hans Kreipe
Philadelphia chromosome-negative chronic myeloproliferative
disorders (Ph- CMPD) comprise a group of heterogenous haematological
stem cell disorders. These diseases harbour a pathological
bone marrow stem cell which overwhelms normal stem cells due
to sustained and uncontrolled proliferation. By clonal evolution,
acute leukaemia or bone marrow fibrosis evolve in a proportion
of cases with as yet unknown underlying mechanisms. Previously,
groundbreaking investigations in Ph- CMPD detected an acquired
mutation in the Janus kinase 2 (JAK2) in the majority of patients
with polycythaemia vera (PV) and in up to 50% of patients
with essential thrombocythaemia (ET) and chronic idiopathic
myelofibrosis (CIMF). Unlike the stem cell defect in Philadelphia
chromosome-positive chronic myeloid leukaemia only a subfraction
of clonally proliferating haematopoiesis may be affected by
the JAK2 mutation. More recently, another mutation in the
juxtamembrane domain of the thrombopoietin receptor Mpl was
discovered in about 5% of patients with CIMF and ET. In accordance
with the uncontrolled Abl kinase activity in Ph+
chronic myloid leukaemia these mutations in Ph- CMPD apparently
represent a key to unlock some of the as yet unknown basic
molecular defects and this raises hope for an upcoming efficient
targeted therapy. However, neither the JAK2V617F
nor the MplW515L/K provide
the initiating molecular events. Moreover, apart from distinction
between reactive and neoplastic lesions, detection of these
mutations does not allow a clear-cut discrimination between
the particular subtypes. This review will focus on previous
and recent findings in the field of molecular defects in Ph-
CMPD.
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