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Stem Cell Treatment for Stroke and Traumatic Brain Injury


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        <p><strong>Damage and Disability caused by Stroke</strong> <br>At
present, ischemic stroke is the third leading cause of death in
industrialised countries. With an annual incidence of 250–400 in 100
000 inhabitants, around 1 million people suffer from a stroke each year
in the United States and in the European Union(1). Approximately a third
of cases are left with some form of permanent impairment, making stroke
the single largest cause of severe disability in the developed world.</p>
<p>Stroke is caused by the interruption of blood flow in a brain-
supplying artery; commonly an embolus causes an occlusion (blockage) in
the blood vessel. Ischemic stroke (cerebral infarction) and the even more
devastating intracerebral haemorrhage, cause a disturbance of neuronal
circuitry and disruption of the blood-brain-barrier that can lead to
functional disabilities. At this time, therapy is primarily based on the
prevention of recurrent (secondary) strokes. Rehabilitation therapy is
important for maximizing functional recovery in the early phase after
stroke, but once recovery has plateaued there is no known treatment.</p>
<p>Stem cell treatment could be the major breakthrough in effecting
repair of some of the damage caused by stroke.<br><br><strong>Cell
transplantation in experimental models of
stroke</strong><br><em>Research: 2001-2008</em><br>Recent studies have
highlighted the enormous potential of cell transplantation therapy for
stroke. A variety of cell types derived from humans have been tested in
experimental/rodent stroke models. Human cells that have been used in
these studies belong in three categories: (i) neural stem cells cultured
from foetal tissue; (ii) immortalised neural cell lines; and (iii)
haematopoietic/endothelial progenitors and stromal cells isolated from
bone marrow, umbilical cord blood or peripheral blood(3).<br><br>While
human embryonic stem cells offer a virtually unlimited source of neural
cells for structural repair in neurological disorders such as stroke,
there are the ethical and safety concerns.Adult neural progenitor cells
can be obtained from different tissues, can be safely expanded in vitro,
and have shown promising therapeutic effects in several neurological
disorders without causing serious side effects(2).</p>
<p>The purpose of this review is to focus specifically on the prospects
of umbilical cord blood cells as stroke therapy.</p>
<p><strong>Review of human umbilical cord blood cell (HUCBC) treatments
for stroke</strong>:</p>
<p>As early as 2001, a study was conducted to assess whether an
intravenous infusion of human umbilical cord blood cells in a rodent
model, could enter the brain, survive, differentiate, and improve
neurological functional recovery at 24 hours and 7 days after stroke. The
study objectives were all achieved to a certain extent(4).</p>
<p>In 2005 a research team at the University of South Florida
investigated strategies to effectively treat stroke patients other than
by re-canalisation of the occluded vessels in the cerebral infarcted
area. This group also investigated strategies to extend the narrow
anticoagulant treatment window to which only a minority of patients have
timely access. The following results were published: rats receiving human
cord blood cells 24 h after stroke demonstrated improvements in
behavioural defects; the 3 hour therapeutic window for anticoagulant
treatment of stroke victims may be extended 24-72 hours post stroke with
the use of umbilical cord blood cell therapy(5).</p>
<p>Paradoxically, a Finnish study (2006) reported that human cord blood
cells, administered intravenously 24 h after stroke in rats, did not
improve functional sensorimotor and cognitive recovery because of limited
migration of cells(6), but that an infusion of pure CD34+ cells following
focal cerebral ischemia demonstrated some improvement in functional
<p>Recently, Kim et al(8) showed that human mesenchymal (CD34+) stem
cells transplanted intravenously (ipsi- and contralateral) into a rat
after ischaemic stroke, possessed the capacity to migrate extensively to
the infarcted area. Promising data were also recently cited for treatment
of intracerebral haemorrhage (ICH): intravenous delivery of cord blood
cells might well enhance endogenous repair mechanisms and functional
recovery after ICH(9, 10).</p>
<p>Current knowledge supports HUCBC as cell transplant candidate for
stroke: It goes without saying that the ideal cell for transplantation
should meet all the criteria of safety for the receiver as well as offer
the highest therapeutic potential. Therapeutic preparations for stroke
require an adequate cell number, which raises the need to expand the
precursor cell source in vitro (cell culture).</p>
<p>• Cord blood is composed of many cell types including haematopoietic
and endothelial stem/progenitor cells (CD34-), mesenchymal cells (CD34+),
immature lymphocytes and monocytes. It is not clear which of these cells
are important for functional recovery after stroke.<br>• Umbilical cord
blood cells, whether delivered intracerebrally or intravenously, target
the ischaemic border. Chemokines - induced by injury - are thought to
mediate this migration process.<br>• Few transplanted cells are found
in the brain, even when delivered intracerebrally. Given the controversy
of whether these cells can really become neurons, it is unlikely that
they act to replace the damaged tissue; it is more feasible that they
secrete factors that enhance inherent brain repair mechanisms(11).</p>
<p>Evidence(review.3) suggests that transplanted cells may work in the
following ways:</p>
<p>• increase vascularisation: Increased blood flow in the ischaemic
area within a few days after stroke is associated with neurological
recovery. The induction of new blood vessel formation (angiogenesis) has
been reported with transplantation of several stem cells including those
from human cord blood.<br>• enhance endogenous (inherent) repair
mechanisms. Human cord blood cells in the ischemic cortex increased
sprouting of nerve fibres.<br>• reduce death of host cells. Several
cell types elicit a neuroprotective effect whereby, presumably by the
secretion of trophic factors, there is often reduction in lesion size and
inhibition of cell death.<br>• reduce inflammation. It has been
reported that stem cells can directly inhibit T-cell activation, thus
inhibiting the immune response. Intravenous injection of human umbilical
cord blood cells reduced leukocyte infiltration into the brain thereby
reducing the stroke-induced inflammatory/immune response.</p>
<p><strong>Clinical Trials</strong></p>
<p>Results: As a consequence of the encouraging results from experimental
studies, pre-clinical phase I and II trials, using different types of
stem cells, were tested in patients suffering from stroke (see <a
rel="nofollow" onclick="javascript:_gaq.push(['_trackPageview',
table.htm" title="table clinical trials">table</a>). Although some of
these trials could demonstrate neurological improvements and cell
transplantations appeared to be a safe procedure, the precise mechanisms
underlying the restorative effects of stem cells were poorly known at the
time of trial(2).</p>
<p>NT2/D1 cells are from a human embryonic carcinoma–derived cell line
and have the capacity to develop into diverse mature nerve-like cells
(LBS neurons; Layton BioScience Inc.) When transplanted, these neuronal
cells survived, extended processes, expressed neurotransmitters, formed
functional synapses, and integrated with the host. Safety and feasibility
of cellular repair were achieved in this setting. Although this small
study was not powered to demonstrate efficacy, valuable data will help in
the design of subsequent clinical trials(3).</p>
<p>Future clinical trials considerations: It has been widely proposed
that further research should focus on the development of new cell lines;
on refining clinical inclusion criteria; on evaluating the need for
immunosuppression; and an evaluation of whether ischemic stroke may be
more suited to cell therapy than haemorrhagic stroke.</p>
<p>• CTX0E03, a human neural stem cell line, has been developed for the
treatment of stable ischemic stroke. The cell line has been tested in
rodent stroke models and in normal nonhuman primates. An application for
a Phase I clinical trial, running for 24 months, has been submitted to
the US Food and Drug Administration and approved.(reported in 1).</p>
<p>• Human umbilical cord blood cells: The use of HUCBC for traumatic
brain injury in children has just been approved (ClinicalTrials.gov
Identifier: NCT00254722). This is the first clinical trial using these
cells for a neurological disorder(reported in 3).</p>
<p>• Timing of transplantation: The brain environment changes
dramatically over time after ischemia. The optimal time to
transplantation after a stroke will depend on the cell type used and
their mechanism of action. If a treatment strategy focuses on
neuroprotective mechanisms, acute delivery of the cells will be critical;
if the cells act to enhance repair mechanisms (e.g. angiogenesis) then
early delivery would be pertinent because these events are most prevalent
in the first 2 to 3 weeks after ischemia; if cell survival is important,
then transplanting late, after inflammation has subsided, could be
<p>• Lesion location and size While experimental data suggest that
recovery from cortical damage may be more complex than from striatal
damage, a conclusive statement can not be made at this point. Precise
anatomic location of the lesion and its functional implication, as well
as lesion size, will be critical determinants to define the target
patient populations for transplantation therapy clinical trials.</p>
<p>Conclusions<br>Stem cell therapy for stroke holds great promise.
However, many fundamental questions related to the optimal candidate
(including the patient age, anatomic location and size of the infarct,
and medical history), the best cell type, the number and concentration of
cells, the timing of surgery, the route and site of delivery, and the
need for immunosuppression remain to be answered. Longer-term studies are
required to determine whether the cell-enhanced recovery is sustained.
Other challenges include ensuring appropriate manufacturing, and quality
control of transplanted cells. Clearly, more research is needed to
translate cell transplantation therapy to the clinic in a timely but safe
and effective manner so that the remarkable potential already shown for
cell transplantation to aid recovery from experimental stroke can become
a reality for the patient(3).</p>
<p>REFERENCES<br>1. Stroke repair with cell transplantation: neuronal
cells, neuroprogenitor cells, and stem cells Kondziolka D, Wechsler L.
Neurosurg Focus. 2008; 24 (3-4):E13.</p>
<p>2 Neural stem cells for the treatment of ischemic stroke Bacigaluppi
M, et al. Journal of the Neurological Sciences 265 (2008) 73–77</p>
<p>3. Cell Transplantation Therapy for Stroke Bliss T, Guzman R, Daadi M;
Steinberg G. Stroke. 2007; 38[2]: 817-826.</p>
<p>4. Intravenous administration of human umbilical cord blood reduces
behavioral deficits after stroke in rats. Chen J, et al. Stroke. 2001; 32
<p>5. Stroke-induced migration of human umbilical cord blood cells Newman
M, et al. Stem Cells Dev. 2005 Oct;14(5):576-86.</p>
<p>6. Human umbilical cord blood cells do not improve sensorimotor or
cognitive outcome following cerebral artery occlusion in rats. Mäkinen
S, Kekarainen T, Nystedt J, et al.. Brain Res. 2006 Dec 6; 1123 (1):207-
<p>7. Human cord blood CD34+ cells and behavioral recovery following
focal cerebral ischemia. Nystedt J, Mäkinen S, et al. Acta Neurobiol
Exp. 2006; 66 (4):293-300</p>
<p>8. In vivo tracking of human mesenchymal stem cells in experimental
stroke. Kim D, et al. Cell Transplant. 2008; 16(10):1007-12.</p>
<p>9. Intravascular cell replacement therapy for stroke Guzman R, Choi R,
Steinberg G et al. Neurosurg Focus. 2008; 24 (3-4):E15.</p>
<p>10. Cell replacement therapy for intracerebral hemorrhage Andres R,
Guzman R, et al Neurosurg Focus. 2008; 24 (3-4):E16.</p>
<p>11. Growth factors, stem cells, and stroke Kalluri H, Dempsey R.
Neurosurg Focus. 2008; 24(3-4):E14.</p>        <!--INFOLINKS_OFF-->

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