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Induced Pluripotent Stem Cells
(iPSCs)
Pluripotent cells make all types of cells
Multipotent cells make some types of cells
unipotent cells make just one type of cells
-Embryonic cells are the most potent but have ethical &rejection problems
-The best days to take the embryo cells are from 4-5 days
Stem Cells and Neurological Disorders
Induced Pluripotent Stem Cells (iPSCs): (By a
Japanese scientist and took the Nobel prize after 5
years of the discovery)
= Retro-differentiation
=
Re-programming
 Producing stem cells from differentiated cells !!!

Pluripotent embryonic like stem cells are produced
 Reversal of normal process
 Does Not require human embryos
 No donor…..No rejection
 Less expensive
 No Ethical issues
Induced means that not naturally
exist and we make it
Pluripotent=acts like embryonic
cell
In this procedure we format
the cell and make it forget its
function and back it to its
native home which is the
embryonic cells
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Main Key Genes:
- iPSCs are derived from adult somatic cells by inducing expression
of certain Stemness genes:
(usually by viral vectors: risk !!!)
- eg: Master transcriptional regulators:
Oct-4
Sox2
Nonog
In each cells there are many genes but
there are just a fraction of them are
active depending on the type of the
cell,so the heart and liver cells have
the same genes but in each of them
some genes have been activated and
the rest are sleepy
- other genes: c-Myc (oncogene: cancer risk !!!!)
These master transcription factor can activate any type of genes but they are
inactivated in differentiated cells so we put an external master transcription gene by a
viral vector and this master key can activate all genes so the cell becomes a
pluripotent cells and the scientists even can make more earlier cells (Totipotent) !!
So from this induced stem cell now we can make any type of cells we want
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Pluripotency:
Believed to be identical to embryonic stem (ES) cells in many respects:
- expression of certain stemness genes
- chromatin methylation patterns
- doubling time
- embryoid body formation
- teratoma formation
- viable chimera formation
- potency and differentiability
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Generation of induced pluripotent stem (iPS) cells
(1) Isolate and culture donor cells.
(2) Transfect stemness genes into cells by viral vectors. Red cells express those genes
(3) Harvest and culture the cells according to ES cell culture, on feeder cells (light gray)
(4) A subset of the transfected cells become iPS cells and generate ES-like colonies
Stem Cells and Neurological Disorders
Neurogenesis of iPS Pluripotent Neuronal Stem Cells
derived from Adult Leukocytes
Potential target disorders for Stem Cell Therapy:
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Leukemia
Heart damage
Anemia
Cornea damage
Retinal damage
Parkinson’s
Alzhimer’s
Diabetes
Spinal Cord Injury
Kidney Failure
Skin grafts
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leukemia
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Heart damage
Injecting a stem cells to the
damaged myocardium and will
return to its work
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Diabetes
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Tissue Engineering
&
Regenerative Medicine
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Bone Repair
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Skin graft grown from stem cells
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Cornea
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trachea from stem cells
In the Trachea and the ear we need a scaffold to
put the stem cells in and then cells will take the shape of the scaffold
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A grown ear seeded with cartilage cells
The scaffold is from a biodegradable matter so when the ear cells finish
replication and take their final form we remove the scaffold
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Stem Cells
&
Neurological Disorders
This is one of the most important aspects of regenerative
medicine because the neurons are postmitotic and cannot
regenerate themselves rather than other tissues
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HSC : Hematopoietic stem cells
MSC : Mesencymal stem cells
Which Stem Cell:
1. Neural stem cells
2. Other Adult SC (HSCs & MSCs)(Plastisity)
3. Cord Blood SC
3. Embryonic SC(Ethical problem)
4. iPSCs
All have been shown to
generate neural tissue
(Adult SCs are the mostly
used in clinical trials)
Delivery Strategy:
1.
2.
Injection into brain
Into Blood stream
Graft type:
1.
2.
(Homing + immobilization by cytokines)
Homing means that the cells know
where to go
Stem cells + Biomaterial (a scaffold that will dissolve)
Stem Cells + Gene therapy (I play with the genes of the stem cells so
a certain chemical will be released more to treat the problem)
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Comparison:
Stem Cell

(Disadvantage)
Embryonic
Pluirpotent
Ethics
Fetal
Pluripotent
Ethics
Cord Blood
Potent
Available
Rejection
Adult Neural / Autologus
Self
Same tissue
low Numbers
Isolation
Adult (HSCs, MSCs,…)
Easy isolation
Easy culture
rejection (if allo.)
Plasticity ?!!
iPCs
Pluripotent
Self
vector safety
From the same person
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Ongoing clinical
Trials in US and
the world 2012
Sanberg et al.
February 2012
Different strategies for stem cell delivery to repair degenerated tissue
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Neural stem cells:
- Generate new neural cells throughout the lifetime
- Can migrate and replace dying neurons
- Give rise to all types of neurons, astrocytes and oligodendrocytes, …
- Capable of only Minor repairs
- Their activity is up-regulated following injury
- Found in:
- Sub-ventricular zone of lateral ventricles
- Dentate gyrus of Hippocampus (2nd)
(Most neurogenic area)
fewer in:
- Cerebellum
- Spinal Cord
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Stem Cells and Neurological Disorders
Therapeutic Applications:
Main target disorders:
- Parkinson’s:
localized degeneration (in substantia nigra) easier cell therapy
- Huntington’s: clear etiology, single gene disorders (Gene/Cell Therapy)
- Alzheimer :
damage is less defined, widespread neuro-degeneration
- Spinal Cord injuries:
- Other:
very promising prospects
- Multiple Sclerosis
- Ischemia / stroke
- Epilepsy
- Amyotrophic Lateral Sclerosis (ALS)
(Siatskas and Bernard, 2009)
(Naegele et al., 2010)
(Wolfson et al., 2009).
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Parkinson’s:
- Main Strategy:
- Replacing degenerated neurons with
dopamine-producing cells
- Site:
- Substantia nigra: area were most degeneration occurs in PD
- Source of SCs:
- Pieces of fetal midbrain tissue
(Mendez et al., 2005)
- Autologous adult neural stem/progenitor cells
- Embryonic SCs
(Michel et al., 2009)
(Friling et al. 2009)
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Huntington’s:
- Good Model: well characterized single gene disorder
- Main Strategy:
Blocking neuronal cell death & replacing lost neurons in striatum
- Source of SCs:
- SCs of fetal striatal primordium into striatum of HD patients
(Bachoud-Lévi et al., 2006)
- Autologous adult neural stem/progenitor cells
(Yu and Silva, 2008; Visnyei et al., 2006).
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Alzheimer’s:
- Neuro-genesis in hippocampus deteriorates in AD patients
Example approaches:
(Lunn et al., 2011)
1. Implanting Neural Stem Cells:
- Replace lost neurons
- Delay degeneration by producing Brain-Derived Neurotrophic Factor (BDNF)
2. Nerve growth factor (NGF) production:
- Genetically engineered patient fibroblasts that produce NGF …!!!
- Integration of NGF fibroblasts into a major cholinergic center of the basal
forebrain provided some benefit to AD patients
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Spinal cord injuries:
(Salewski et al., 2010; Hu et al., 2010, Mathai et al 2008).
Stem cells can:
1. Replace neurons that died from injury
2. Generate supporting cells to re-form the myelin sheath & stimulate regrowth of damaged nerves
3. Protect cells at injury site from further damage, by releasing protective factors
Stem cells under trials:
- Embryonic SCs
- Umbilical cord SCs
- Adult neural SCs
- Mesenchymal / bone marrow SCs
- induced pluripotent Scs
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Christopher Reeve
1952 - 2004
Stem Cells and Neurological Disorders
Paralyzed Patients Walking Again
http://www.youtube.com/watch?v=KGUAyKQKmmY
http://www.youtube.com/watch?v=-kygF2leZCE
http://www.youtube.com/watch?v=ZgI4tm8Tr5M
Stem Cells and Neurological Disorders
Conclusion:
- Very promising clinical trial results in the last few years
- More research needed to optimize diff. SC replacement protocols:
- Cell type
- Route
- No. of cells
- Single or multiple cell doses
- Choice between ESCs / ASCs / iPSCs:
- Ethics (ESCs and Fetal tissue):
yet to be resolved
Each Country has to decide
Stem Cells and Neurological Disorders
THANK YOU
Stem Cells and Neurological Disorders