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Induced Pluripotent Stem Cells

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Induced Pluripotent Stem Cells

(iPSCs)Pluripotent cells make all types of cellsMultipotent cells make some types of cellsunipotent 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

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Induced Pluripotent Stem Cells (iPSCs): (By a Japanese scientist and took the Nobel prize after 5 years of the discovery)= Retro-differentiation = Re-programming

Induced means that not naturally exist and we make itPluripotent=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

  • 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

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Main Key Genes:

  • iPSCs are derived from adult somatic cells by inducing expression
  • of certain Stemnessgenes: (usually by viral vectors: risk !!!)
  • - eg: Master transcriptional regulators:
  • Oct-4Sox2
  • 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

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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

Stem Cells and Neurological Disorders

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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

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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

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leukemia

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Injecting a stem cells to the damaged myocardium and will return to its work

Heart damage

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Diabetes

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Tissue Engineering

&

Regenerative Medicine

Stem Cells and Neurological Disorders

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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 cellsThe 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

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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 cellsMSC : 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

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Comparison:

  • Stem Cell  (Disadvantage)
  • EmbryonicPluirpotent Ethics
  • FetalPluripotent Ethics
  • Cord Blood Potent Rejection
  • Available
  • Adult Neural / Autologus Self low Numbers Same tissue Isolation
  • Adult (HSCs, MSCs,…) Easy isolation rejection (if allo.) Easy culturePlasticity ?!!
  • iPCsPluripotent vector safety
  • Self

From the same person

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Ongoing clinical

Trials in US and

the world 2012

Sanberg et al.

February 2012

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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 (Most neurogenic area)
  • - Dentate gyrus of Hippocampus(2nd)
  • fewer in:
  • - Cerebellum
  • - Spinal Cord

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Therapeutic Applications:

  • Main target disorders:
  • - Parkinson’s: localized degeneration (in substantianigra) easier cell therapy
      • Huntington’s: clear etiology, single gene disorders (Gene/Cell Therapy)
      • Alzheimer : damage is less defined, widespreadneuro-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).

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Parkinson’s:

  • Main Strategy:
  • - Replacing degenerated neurons with
  • dopamine-producing cells
  • Site:
  • - Substantianigra: 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)

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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 fetalstriatalprimordium 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 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 pluripotentScs

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Christopher Reeve

1952 - 2004

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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

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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

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THANK YOU

Stem Cells and Neurological Disorders

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