1. Induced Pluripotent Stem Cells Stem Cells and Neurological Disorders
(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

2. 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
Stem Cells and Neurological Disorders

3. Stem Cells and Neurological Disorders
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
- other genes: c-Myc (oncogene: cancer risk !!!!)
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
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
Stem Cells and Neurological Disorders

4. Stem Cells and Neurological Disorders
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
Stem Cells and Neurological Disorders

5. Stem Cells and Neurological Disorders
Generation of induced pluripotent stem (iPS) cells
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

6. Neurogenesis of iPS Pluripotent Neuronal Stem Cells derived from Adult Leukocytes

7. Stem Cells and Neurological Disorders
Potential target disorders for Stem Cell Therapy:
Leukemia
Heart damage
Anemia
Cornea damage
Retinal damage
Parkinson’s
Alzhimer’s
Diabetes
Spinal Cord Injury
Kidney Failure
Skin grafts
Stem Cells and Neurological Disorders

8. Stem Cells and Neurological Disorders
leukemia
Stem Cells and Neurological Disorders

9. Stem Cells and Neurological Disorders
Injecting a stem cells to the damaged myocardium and will return to its work
Heart damage
Stem Cells and Neurological Disorders

10. Stem Cells and Neurological Disorders
Diabetes
Stem Cells and Neurological Disorders

11. Regenerative Medicine Stem Cells and Neurological Disorders
Tissue Engineering
&
Regenerative Medicine
Stem Cells and Neurological Disorders

12. Stem Cells and Neurological Disorders
Bone Repair
Stem Cells and Neurological Disorders

13. Stem Cells and Neurological Disorders
Skin graft grown from stem cells
Stem Cells and Neurological Disorders

14. Stem Cells and Neurological Disorders
Cornea
Stem Cells and Neurological Disorders

15. Stem Cells and Neurological Disorders
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
Stem Cells and Neurological Disorders

16. Stem Cells and Neurological Disorders
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
Stem Cells and Neurological Disorders

17. Neurological Disorders Stem Cells and Neurological Disorders
&
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
Stem Cells and Neurological Disorders

18. Which Stem Cell: Delivery Strategy: Graft type:
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
Delivery Strategy:
Injection into brain
Into Blood stream (Homing + immobilization by cytokines)
Graft type:
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)
All have been shown to
generate neural tissue
(Adult SCs are the mostly
used in clinical trials)
Homing means that the cells know where to go
Stem Cells and Neurological Disorders

19. Stem Cells and Neurological Disorders
Comparison:
Stem Cell  (Disadvantage)
Embryonic Pluirpotent Ethics
Fetal Pluripotent Ethics
Cord Blood Potent Rejection
Available
Adult Neural / Autologus Self low Numbers Same tissue Isolation
Adult (HSCs, MSCs,…) Easy isolation rejection (if allo.) Easy culture Plasticity ?!!
iPCs Pluripotent vector safety
Self
From the same person
Stem Cells and Neurological Disorders

20. Ongoing clinical
Trials in US and
the world 2012
Sanberg et al.
February 2012

21. Stem Cells and Neurological Disorders
Different strategies for stem cell delivery to repair degenerated tissue
Stem Cells and Neurological Disorders

22. Stem Cells and Neurological Disorders
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 (Most neurogenic area)
- Dentate gyrus of Hippocampus (2nd)
fewer in:
- Cerebellum   
- Spinal Cord
Stem Cells and Neurological Disorders

23. Stem Cells and Neurological Disorders

24. Stem Cells and Neurological Disorders

25. 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: very promising prospects
Other: - Multiple Sclerosis (Siatskas and Bernard, 2009)
Ischemia / stroke
Epilepsy (Naegele et al., 2010)
Amyotrophic Lateral Sclerosis (ALS) (Wolfson et al., 2009).
Stem Cells and Neurological Disorders

26. Stem Cells and Neurological Disorders
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 (Michel et al., 2009)
- Embryonic SCs (Friling et al. 2009)
Stem Cells and Neurological Disorders

27. Stem Cells and Neurological Disorders
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).
Stem Cells and Neurological Disorders

28. Stem Cells and Neurological Disorders
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
Stem Cells and Neurological Disorders

29. Stem Cells and Neurological Disorders
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 re-
growth 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
Stem Cells and Neurological Disorders

30. Stem Cells and Neurological Disorders
Christopher Reeve
Stem Cells and Neurological Disorders

31. Paralyzed Patients Walking Again Stem Cells and Neurological Disorders
Stem Cells and Neurological Disorders

32. 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: yet to be resolved
Ethics (ESCs and Fetal tissue): Each Country has to decide
Stem Cells and Neurological Disorders

33. Stem Cells and Neurological Disorders
THANK YOU
Stem Cells and Neurological Disorders