The application of stem cells
To Lysosomal Storage Disorders,
Morbus Duchenne, Erythroblastosis fetalis,
Potter’s Syndrome and the
Ethical issues behind it.
By
Dorit Hasselberg
Pass
James Jones
Pass
Research paper
Based on
Pathology lectures
At Medlink 2011
Page 1
Abstract
With more research into stem cells there are many new applications to existing diseases and syndromes
available, for example, stem cells have been, and still are, used in treatment of cancer, to replace cells destroyed
by radiation or chemotherapy. Stem cells are, at the moment, rarely used in medicine, as research into such
treatments is hampered by tough ethical opposition against the obtaining of stem cells from live embryos or
foetus’, usually killing both embryo and foetus after the stem cells have been extracted. There are always new
discoveries into treatments and possible methods of stem cell harvesting, but due to lack of funding and legal
obstacles many promising ideas may not be realized.
This paper is on the possible application of stem cells to reduce, or annihilate the effects of Lysosomal
disorders, muscular dystrophy Duchenne, Rhesus incompatibility and Potter’s syndrome, by replacing the cells
which have been lost, or to allocate tissues missing yet needed, and some of the ethical issues blocking research
into new treatments and possible ways around these problems.
Introduction
a) definition of stem cell and actual state of research
A stem cell is “A cell that has the ability to continuously divide and differentiate (develop)
into various other kind(s) of cells/tissues”1 2
Stem cells can be obtained by different methods. Embryonic stem cells are collected from the
inner layer of a 4-to-7 day-old embryo, a blastocyst; these cells often are pluripotent, seldom
totipotent. The embryo is generally destroyed by this way of stem cell collection. Totipotent
cells can be gained by transferring an adult nucleus into an enucleated stem cell or ovule, as it
was made for the sheep Dolly; the genes of this nucleus seem to redevelop embryonic
properties by this transfer. This procedure shows the advantage that the resulting cells have
the same tissue markers as the donor of the (adult) nucleus, avoiding rejection. As a third
possibility, embryonic pluripotent cells are found as embryonic germ cells in aborted foetuses
or embryos. The umbilical cord, cord blood or the placenta are also used as sources for
pluripotent stem cells. Many enterprises profit of the parents´ wish to get the most safety for
their newborn child offering them to conserve cells of the child’s umbilical cord blood, in
case of a later malignant disease3, and the fact that cord blood, placentas and other cord
materiel are abundantly available, unlike ovules and embryos, is very much in favour of these
techniques.
Adult stem cells can be identified in different tissues, as in bone marrow, but they are also
found in other tissues like muscles, mesenchymal or nerve 4 5 and are also subject to actual
and further investigations.
Some researchers use viruses to induce a permanent growth and replication of stem cells like
a cancer; others use drugs to introduce this genetic information or to reprogram them.6
Different proteins or polypeptides also responsible of maintaining the pluripotency of
embryonic stem cells (ESC) predict and control the choice of one of the three embryonic
tissue layers, these mechanisms are object to continuous research, as knowing and controlling
the development of special tissues is basic for their therapeutic use.7 8 9 Even well known
substances as ascorbic acid were shown to play a role in tissue differentiation, for example
1
http://www.godandscience.org/slideshow/stem002.html
http://www.drze.de/im-blickpunkt/stammzellen
3
http://bimbomarket-en.blogspot.com/2009/09/conservation-of-stem-cells-from.html
2
4
http://www.dfg.de/download/pdf/dfg_im_profil/reden_stellungnahmen/archiv_download/eszell_d_99.pdf
5
http://www.brainlife.org/reprint/2003/galli_r030404.pdf
6
http://www.sciencemag.org/content/322/5903/949.short
7
http://bts.ucsf.edu/chen/files/0009.pdf
8
http://www.cell.com/abstract/S0092-8674(11)00543-5
9
http://www.genomics.princeton.edu/tank/pdf-publications/Nature%20336,%20677-680%20(1988)..pdf
Page 2
cardiac myocytes. The location where stem cells are grown also plays an important role for
the development and differentiation, the so-called niche, a condition that is difficult to imitate
in a laboratory.10
There have been many attempts to transfer missing or amended genetic material (DNA/RNA)
into human tissue in order to produce missing hormones, like insulin, missing coagulation
factors (VIII or IX) or substances to reduce inflammation. This genetic material can be
transferred by manipulated viruses infecting human tissues, or wrapped by a liposome. As
this kind of transferring DNA is not very effective, there have been other methods using
modified stem cells: the genetic information is put (by viruses) into stem cells, these cells are
multiplied and transformed into the kind of tissue which sticks to other tissues in need of
treatment. So the genetic information can be transferred into the patient like a simple blood
transfusion. If stem cells from the same individual are used, there will be no risk of rejection,
as there would be in the case of exogenous cells.11
b) actual use of stem cells in medicine
There have been several studies about muscle stem cell transplantation as a possible
treatment to improve myocardial function. It has shown certain benefits on ventricular
remodelling and improves perfusion in the infarct area, though the effects are very modest.
However, it seems more difficult to connect the new myocardial cells to the Purkinye
fibres, as there was a certain risk of arrhythmia after transplantation. So both the benefits
and the arrhythmogen effects are still being researched. 12 13 14 15
There is an enormous variety of chronic inflammations of the kidney. Bone marrow stem
cells previously infected with a virus transfected with a therapeutic gene can be recruited to
the inflamed glomeruli where they may deliver anti-inflammable cytokines. That was shown
to be effective in anti- GBM nephritis in mice. The advantage of this treatment is the
possibility of using the patient’s own bone marrow stem cells, avoiding immunoreactions.
Other studies showed that injecting renal stem cells in the renal artery could lead to glomeruli
proliferation and a certain repair,16 whereas injecting non-stem cells did not show such an
effect.17
There are also many serious illnesses concerning the nervous system, where stem cell
research is concerned.
The Huntington’s disease is a genetic disease including behavioural disturbances and
movement problems with a hyperkinetic and hypotonic disturbance leading to an early
death within 15 to 20 years. As another example, in Parkinson disease, a very common
neurological disease in older people, there is a progressive loss of specific cells producing
the hormone dopamine, causing shivering and a hypo kinetic and rigid syndrome. In both
cases medicaments can help to a certain extent and reduce symptoms until too many
neurons are damaged. There have been clinical trials of using stem- cells to replace the
medium spiny neurons in the case of the Huntington’s or in the corpus striatum for the
10
http://www.sciencedirect.com/science/article/pii/S0955067404001395
http://stemcells.nih.gov/info/scireport/chapter11.asp
12
http://www.annals.org/content/140/9/729
13
http://www.medscape.com/viewarticle/735168
14
http://www.nature.com/cdd/journal/v14/n7/full/4402146a.html
15
http://health.nytimes.com/health/guides/disease/glomerulonephritis/overview.html
16
http://www.springerlink.com/content/ph4urf5atg3lupq2/
11
17
http://jasn.asnjournals.org/content/17/8/2202.short
Page 3
Parkinson disease,18 or to transplant stem cells releasing a neurotrophic factor to protect
and regenerate neurons.19 Especially in the case of Huntington’s disease, there might be a
great demand of treatment, as this illness can be detected by genetic diagnostics a long
time before it breaks out, so people affected are generally horrified by the secure fate of
their mental degradation and can still judge themselves- as far as possible- about the
possible side effects of such a treatment, whereas other dementia patients need someone
else to decide for them.20 21 22 There have also been trials for Alzheimer’s disease, for
Lysosomal storage disorders, and other enzymatic diseases as well as multiple sclerosis
and strokes, or spinal cord injuries23, diseases with a loss of functional tissue. In each case,
endogenous and exogenous stem cells have been used on individual experimental basis
showing inconsistent effects.24 In other studies, the effects of stem cells modifying a
current inflammatory process in the CNS were discussed, showing perspectives for future
research.25
There are several types of blood cancer, Leukaemia, Myeloma, Lymphoma and Hodgkin’s
disease, all of them possibly lethal. Normally these diseases are treated by radiation and
chemotherapies but in case of treatment failure it is often the last chance for the patient to
receive a bone marrow stem cell transplantation replacing his own. In contrast to the
previously mentioned applications of stem cells, this is a quite regularly practised therapeutic
option. As usually exogenous stem cells are transferred, similar tissue markers of donor and
patient in order to prevent a rejection or a graft- versus- host- reaction are required. This stem
cell treatment is relatively easy in comparison to the experimental treatments mentioned
above, as the bone marrow stem cells are expected to become just a bone marrow and do not
need to be programmed into becoming another cell type.26 27
Discussion
The European court decided in October 2011 that procedures involving embryonic stem cells
cannot be patented. “The environmental group argued that Brüstle's work was "contrary to
public order" because embryos were destroyed to gather the stem cells used.”28
This decision makes it less attractive for a lot of firms to invest in stem cell research and
more difficult to obtain results in therapy.29 30
This is worth a more detailed look at the reasons for this decision:
Embryonic stem cells can only be obtained by killing the embryo.
18
http://onlinelibrary.wiley.com/doi/10.1002/jnr.22054/full
http://celleng.sjtu.edu.cn/pic/xq17.pdf
20
http://www.innovations-report.de/html/berichte/medizin_gesundheit/bericht-17742.html
19
21
22
http://www.albrecht-kossel-institut.de/en/Teaching/Module4a/12-Clinical-Application-of-Stem-Cells-II.pdf
http://www.nlm.nih.gov/medlineplus/ency/article/000770.htm
23
http://onlinelibrary.wiley.com/doi/10.1002/jnr.22054/full
24
http://journals.lww.com/neurosurgery/Abstract/2004/08000/Genetic_and_Cellular_Therapies_for_Cerebral.3.a
spx
25
http://www.nature.com/nrn/journal/v7/n5/abs/nrn1908.html
26
http://www.yorkagainstcancer.org.uk/learn-about-cancer/types-of-cancer/haematological-cancer/
27
http://www.intechopen.com/source/pdfs/26995/InTechHematopoietic_stem_cell_in_acute_myeloid_leukemia_development.pdf
28
http://www.heise.de/tp/artikel/35/35715/1.html
29
http://www.zeit.de/wissen/2011-10/eugh-stammzellen-urteil
30
http://www.guardian.co.uk/science/2011/oct/18/european-patents-embryonic-stem-cells
Page 4
The first problem is how to define an embryo, - can we call it an embryo as soon as there are
the first organs formed and the development of the brain or does it start at the moment of the
fusion of the maternal and paternal nuclei? The human rights protect every human life and
dignity. Furthermore, many countries forbid cloning human life judging this science-made
life unethical, so the production of totipotent cells from adult tissues might be the first step to
creating an embryo with the same properties as the original adult- as it was shown in Dolly,
the sheep. So therapeutic cloning, as it is allowed in UK, is forbidden in other countries, like
Germany. As no further ingredient (except the maternal body) is necessary to make a
complete human life of a fecundated ovule, the European Court attributed the full legal
protection to each embryo. It would be nearly impossible to control that women don’t sell
their ovules for money, especially in poor countries, the act of gaining them still being a
certain health risk to the donor. One personal comment might be allowed: One of us was born
from an ovule fecondated in a Petri dish, being the last of 30 thus fecondated and transferred
ovules. If the parents had consented (under the understandable strong impression to owe the
doctors for the first successful treatment) to donate the last fecondated ovules after the first
apparently successful attempt of transferring 3 of them, this author would not exist- and
maybe even no other child instead. And how can we know at which degree donating ovules
or embryos is really voluntary and deliberate- without a chance for them to become a human,
some years later? At which extend can their parents predict their future will?
But on the other hand, many lethal diseases cannot be cured with conventional
medicaments and require a well founded research. Over more, research has to be widely
spread in order to find the best and most secure treatment- a dilemma where compromises are
to be found.
A possible way could be to define illnesses which need innovative, genetic and/or stem cell
treatment in first line. Second, methods of controlling the origin of these stem cells should be
found to protect embryos or ovules from being sold or demanded. Abortions must not be
favorised by financial stimulus, neither in foreign countries with lower income levels.
There is another considerable risk in stem cells: As they can divide themselves continuously,
they might also develop into a cancer, as it was shown in mice;31 describing a teratoma after a
stem cell treatment of diabetes. Diabetes lessens life quality and might even shorten life, but
many patients might it not find worth the risk of developing tumours as a side effect. From
our point of view, diseases leading to an early death in childhood fulfil best the first
conditions, so we would like to concentrate on 4 examples for further useful research,
although this might mean that these illnesses are not as frequent and as medially discussed as
Alzheimer, for example, and might arouse the problem of not finding the necessary financial
resources for research.32 33
Among lethal metabolic illnesses, lysosomal and peroxisomal storage disorders occupy an
important range, some of them treatable with medicaments, but most of them lead to loss of
abilities and early death in childhood.34 As most of them are genetically transmitted, an early
diagnosis before the first symptoms in familiar cases is possible, offering the possibility to
conserve neurons and other organs rather than repairing them. In many forms of storage
diseases, not only neurons but also bones, liver, spleen and other organs show symptoms, as
an enzyme necessary for degrading metabolic products is missing in all of these cells. Some
centres offer a genetic treatment transferring the lacking DNA via viruses into the different
31
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1602425/
http://emedicine.medscape.com/article/1182830-overview
33
http://neuropathology-web.org/chapter10/chapter10bLSDs.html
34
http://emedicine.medscape.com/article/1182830-overview
32
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cells, but the effect is short and limited by antibodies against the used viruses35 36. Actual
stem cell treatment consists in transferring bone marrow generated cells37 which are able to
produce the lacking enzyme and improve many organic symptoms, but neurological and bone
symptoms often persist. Hence it might be necessary to transfer more specialised cells, i.e.
manipulated neural or glia stem cells38, into the brain as the determining organ to improve
cerebral functions. In order to prevent rejection, cells should derive from the patient himself,
but should contain a transferred genome with the necessary information for the lacking
enzyme. If transplantation can be done early, the manipulated stem cells could be integrated
among the “normal” cells producing enough enzymes for both types of cells. 39 Thus further
degradation could be prevented, and as in the brain of very young children most neurons still
form their synapses40, an integration and proliferation of functioning cells would be more
prosperous than in adult brains, where the neuronal network is more fixed. So the transferred
cells could not only work as enzyme producer for the others but also replace them in their
original function41.
Another disease worth further research is Muscular Dystrophy Duchenne, a progressive loss
of skeleton muscles, x- linked recessive and so concerning boys. In early age of childhood,
muscles start disappearing, leading to immobilisation in wheel chair at about the age of 12
years and death by suffocating, due to a loss of muscle cells in the diaphragm. Available
treatments are limited to alleviate the symptoms, but it cannot extend life time. Stem cells
could help by transferring manipulated muscle cells into the patient’s muscles.42 43 Studies
have shown an effect of mesangioplast stem cells integrating in muscles of concerned mice
and sometimes in dogs44 45 ,improving muscle function, so there could be a possibility for
humans, too, as the stem cells were given by transfusion,46 thus integrating in any other type
of skeleton muscle, conserving the complicated balance of antagonist muscles and reaching
the diaphragm, too. Transfusion of cord blood stem cells did not work, though.47 Here other
techniques should be investigated either to use manipulated autonomic stem deriving from
the patient, in order to prevent rejection, containing a genetic information needed by the
patient’s muscles. Muscle cells generally fuse, uniting many nuclei in one muscle cell, so the
manipulated and transplanted stem cells might stick to them, then fuse and amend the
function of each fibre.
A quite frequent illness in pregnancy and newborn children is erythroblastosis fetalis 48, a
haemolytic disease caused by antibodies against the rhesus property of the foetus´
erythrocytes. Normally rhesus-negative women have no antibodies against the Rhesus
properties of other person’s blood, but during a preceding birth or abortion, there may be
such a blood contact that creates a constant and even growing production of antibodies that
35
http://www.jci.org/articles/view/36521
http://pediatrics.aappublications.org/content/123/4/1191.full#sec-15
37
http://www.springerlink.com/content/3ejm635wgyrdg0lp/
38
http://onlinelibrary.wiley.com/doi/10.1002/jnr.22054/full
39
http://www.pedneur.com/article/S0887-8994(03)00434-X/abstract
40
http://umaine.edu/publications/4356e/,
41
http://www.jci.org/articles/view/36521
42
http://www.nhs.uk/Conditions/Muscular-dystrophy/Pages/Treatment.aspx
43
http://www.nature.com/mt/journal/v18/n2/full/mt2009274a.html
44
http://bloodjournal.hematologylibrary.org/content/104/13/4311.short
45
http://www.nature.com/nature/journal/v444/n7119/abs/nature05282.html
46
http://www.sciencemag.org/content/301/5632/487.short
47
http://neurology.jwatch.org/cgi/content/full/2010/831/1
48
http://adc.bmj.com/content/67/1_Spec_No/65
36
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get into the foetus attacking its erythrocytes. If the level of antibodies is low, rhesus- positive
children will only develop minor symptoms like yellow skin. But rhesus negative mothers not
having been treated properly after a former pregnancy are susceptible to develop high levels
of antibodies destroying foetal red blood cells, and these children may develop such a severe
anaemia that they risk death during pregnancy by this anaemia, an illness called hydrops
fetalis. When diagnosed early, these children may be saved by transfusions of rhesus negative
erythrocytes into their body or their cord, and these transfusions may be necessary,
repeatedly49, though there is a high risk of bleeding or hurting the foetus. If it was possible to
transfer rhesus negative stem cells of the same tissue properties as the patient, the child might
be able after only one risky transfusion to form its own un-attackable erythrocytes, thus
preventing the risks of a premature birth and especially prenatal death. Maybe this treatment
is possible in a nearer future, as scientists already have gained certain experiences with bone
marrow stem cells and intra-cord transfusions before birth. Here it might be an advantage that
transferred stem cells do not always survive as long as original cells: The mortal danger ends
at birth, and the child’s maturing immune system is well come to destroy the transplanted
cells.50
Another disease leading to death even directly at birth is Potter’s Syndrome. A complete, or
functional, lack of kidneys in the foetus leads to a secondary lack of urine and therefore of
amniotic liquid, so the lung cannot develop properly, which means death by suffocation after
birth. There is no actual treatment possible,51 but awaiting death at birth or an induced
abortion is ethically no alternative to an eventual curative treatment. In case of very early
prenatal genetic diagnosis, it might be possible in the future to inject stem cells into the
embryo or the cord programmed to develop into the complete organ system (kidneys, vessel,
ureters and urethra). Up to now, no complete organs could be created by culturing stem cells,
and many determinant factors for programming pluripotent cells are not known, yet, but it
might be that in the natural environment of an embryonic body stem cells can find their way
more easily, and it seems that it depends also on the niche where stem cells are whether they
develop into a certain tissue or an other. Rejection might be a problem, as no tissue can be
gained from the child, but as the child’s immune system is not mature at this early stage of
pregnancy, it is hoped that mechanisms can be found to make sure exogenous cells might be
integrated and tolerated without rejection.52 - These children have no other chance of any
postnatal life, so ethical objections should not exist on the basis of the taking of life from a
possible human being.
In contrast to these quite rare, but grave illnesses, there are many others which could also
profit of a stem cell therapy and which are so frequent that they cause high costs for the
health services, e.g. diabetes 53 54, but these illnesses do not shorten life in the same measure,
so therapies should essentially be tried with stem cells of adult or placenta cord origin, and as
there might always be a risk of uncontrollable growth, as it was shown in a case of teratoma
in stem-cell treated mice, further research must examine how to control the multiplication of
transferred cells as well55 as their differentiation. Another example is different forms of
arthrosis or arthritis. Cartilage in the articulations has only a very low ability to mend itself
49
http://www.nejm.org/doi/pdf/10.1056/NEJM198605293142207
http://www.nejm.org/doi/full/10.1056/NEJM196410012711403
51
http://jama.ama-assn.org/content/246/6/635.short
52
http://www.patient.co.uk/doctor/Potter's-Syndrome.htm
53
http://www.nhs.uk/news/2009/04April/Pages/StemCellDiabetesTreatement.aspx
54
http://diabetes.diabetesjournals.org/content/50/8/1691.short
55
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1602425/
50
Page 7
once it was destroyed by inflammation, accidents or old age. Many people suffer severe pain
in their articulations, leading to a premature retirement. It should be possible to inject
cartilage precursor cells won from the patient´s bone marrow for example, into the concerned
articulation as it was shown,56 preventing immobilisation and loss of income. Even other
tissues, i. e. tendons, bones with non-healing fractures or tumorous destruction or
intervertebral disks could be repaired this way.57
In contrast to these somatic applications, there are also researches to treat mental illnesses, for
example depressions or schizophrenia. . In some cases these illnesses seem to be caused by
problems of differentiation or migration of neurons, so homologous, manipulated neural stem
cells might help. But ethical problems arouse when results might be misused to alter
undesirable people in the opinion of any powerful criminal or a government not respecting
the human rights. If a personality risks to be altered in a way the patient does not want by
injecting allogeneic cells, these experiments should not take place. So from our point of view
treatments of that kind should underlie a strict ethical control, both concerning to the
procedure itself and the possibilities of misuse.58 59
Conclusion
There are many perspectives in stem cell research, and it seems that therapies are possible
with cells of very different origin, be embryonic, foetal, more easily available as deriving
from cord jelly, cord blood or placenta, or of adult origin like bone marrow, neural or other
locations. The more an illness limits life length or causes long suffering, the more urgently
research should be emphasized. Ethically we think that both somatic cells and afterbirth
collection of placenta and cord material are largely preferable, but as long as the
mechanisms to control the development of a pluripotent cell or the induction of a
pluripotent state of adult somatic cells are not completely understood, it might be necessary
to use embryonic or therapeutically cloned cells on basis of ovules to explore the
mechanisms. We also think that the gaining of stem cells from a foetus is not entirely
wrong, as long as the parents have given consent and there is no pressure or incentive from
larger organisations which would profit in any way from the gaining of more stem cells to
research or use in medical treatments. As long as possible, the embryonic stem cells which
are already available should be used in first line to prevent ethical dilemmas, and in case
researchers are in need of new cells, as Brüstle demands it urgently, sources for ovules
must submit a severe control. We agree that the harvesting of stem cells from a foetus with
prominent symptoms of Potters Syndrome can be justified, as long as there is no cure
possible and as the child would have no chance of survival, until a future treatment, with
the ability to grow the missing kidneys of the child, possibly through application of stem
cells. If possible, stem cells should be used that do not derive from fresh embryos in order
not to induce abortions.
Aside from the ethics of stem cell harvesting there are also the prospects of applying stem
cells to existing conditions, such as Huntington’s disease, the application of stem cells may
be used to replicate the lost cells, prolonging life and reducing the symptoms of such
conditions, helping also to prolong the life of the sufferer further, but also to ensure that
time gained is not still in the comfort of as good health the condition can offer. We also
agree it is important for research into the location, and usage of stem cells to continue at its
56
http://www.pnas.org/content/100/suppl.1/11917.short
http://www.nature.com/gt/journal/v11/n4/abs/3302197a.html
58
http://www.springerlink.com/content/ly73cv1eefyb4tt5/
59
http://onlinelibrary.wiley.com/doi/10.1111/j.1601-5215.2007.00176.x/full
57
Page 8
current pace, or, better so, for ethical restrictions to be lifted so more research can be done
to find cures to such afflictions as Huntington’s disease, leukaemia, myeloma and
Hodgkin’s disease.
Links used:
http://www.godandscience.org/slideshow/stem002.html
http://www.drze.de/im-blickpunkt/stammzellen
http://bimbomarket-en.blogspot.com/2009/09/conservation-of-stem-cells-from.html
http://www.dfg.de/download/pdf/dfg_im_profil/reden_stellungnahmen/archiv_download/esze
ll_d_99.pdf
http://www.brainlife.org/reprint/2003/galli_r030404.pdf
http://www.sciencemag.org/content/322/5903/949.short
http://bts.ucsf.edu/chen/files/0009.pdf
http://www.cell.com/abstract/S0092-8674(11)00543-5
http://www.genomics.princeton.edu/tank/pdf-publications/Nature%20336,%20677680%20(1988)..pdf
http://www.sciencedirect.com/science/article/pii/S0955067404001395
http://stemcells.nih.gov/info/scireport/chapter11.asp
http://www.annals.org/content/140/9/729
http://www.medscape.com/viewarticle/735168
http://www.nature.com/cdd/journal/v14/n7/full/4402146a.html
http://health.nytimes.com/health/guides/disease/glomerulonephritis/overview.html
http://www.springerlink.com/content/ph4urf5atg3lupq2/
http://jasn.asnjournals.org/content/17/8/2202.short
http://onlinelibrary.wiley.com/doi/10.1002/jnr.22054/full
http://celleng.sjtu.edu.cn/pic/xq17.pdf
http://www.innovations-report.de/html/berichte/medizin_gesundheit/bericht-17742.html
http://www.albrecht-kossel-institut.de/en/Teaching/Module4a/12-Clinical-Application-ofStem-Cells-II.pdf
http://www.nlm.nih.gov/medlineplus/ency/article/000770.htm
http://onlinelibrary.wiley.com/doi/10.1002/jnr.22054/full
http://journals.lww.com/neurosurgery/Abstract/2004/08000/Genetic_and_Cellular_Therapies
_for_Cerebral.3.aspx
http://www.nature.com/nrn/journal/v7/n5/abs/nrn1908.html
http://www.yorkagainstcancer.org.uk/learn-about-cancer/types-of-cancer/haematologicalcancer/
http://www.intechopen.com/source/pdfs/26995/InTechHematopoietic_stem_cell_in_acute_myeloid_leukemia_development.pdf
http://www.heise.de/tp/artikel/35/35715/1.html
http://www.zeit.de/wissen/2011-10/eugh-stammzellen-urteil
http://www.guardian.co.uk/science/2011/oct/18/european-patents-embryonic-stem-cells
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1602425/
http://emedicine.medscape.com/article/1182830-overview
http://neuropathology-web.org/chapter10/chapter10bLSDs.html
http://emedicine.medscape.com/article/1182830-overview
http://www.jci.org/articles/view/36521
http://pediatrics.aappublications.org/content/123/4/1191.full#sec-15
http://www.springerlink.com/content/3ejm635wgyrdg0lp/
http://onlinelibrary.wiley.com/doi/10.1002/jnr.22054/full
Page 9
http://www.pedneur.com/article/S0887-8994(03)00434-X/abstract
http://umaine.edu/publications/4356e/,
http://www.jci.org/articles/view/36521
http://www.nhs.uk/Conditions/Muscular-dystrophy/Pages/Treatment.aspx
http://www.nature.com/mt/journal/v18/n2/full/mt2009274a.html
http://bloodjournal.hematologylibrary.org/content/104/13/4311.short
http://www.nature.com/nature/journal/v444/n7119/abs/nature05282.html
http://www.sciencemag.org/content/301/5632/487.short
http://neurology.jwatch.org/cgi/content/full/2010/831/1
http://adc.bmj.com/content/67/1_Spec_No/65
http://www.nejm.org/doi/pdf/10.1056/NEJM198605293142207
http://www.nejm.org/doi/full/10.1056/NEJM196410012711403
http://jama.ama-assn.org/content/246/6/635.short
http://www.patient.co.uk/doctor/Potter's-Syndrome.htm
http://www.nhs.uk/news/2009/04April/Pages/StemCellDiabetesTreatement.aspx
http://diabetes.diabetesjournals.org/content/50/8/1691.short
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1602425/
http://www.pnas.org/content/100/suppl.1/11917.short
http://www.nature.com/gt/journal/v11/n4/abs/3302197a.html
http://www.springerlink.com/content/ly73cv1eefyb4tt5/
http://onlinelibrary.wiley.com/doi/10.1111/j.1601-5215.2007.00176.x/full
Page
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