Download Stem Cells

Stem cells and neuroscience:
Biology, applications, and
controversy
Noam Y. Harel, MD, PhD
12 November 2013
Brain and Behavior
Disclosures
• I do not have any financial or other
conflicts of interest to disclose for this
learning session.
• I do not affirm that all discussions of
drug use will be consistent with either
FDA or compendia-approved
indications. Off-label and experimental
drugs may be discussed.
Learning Objectives
1. Understand the origin and potential tissue types
created by different classes of stem cells.
2. Understand the potential benefits and risks of
stem cell applications.
3. Become versed in discussing the questions that
will frequently be raised by patients regarding
stem cells.
Strategery: Repair and Recovery
Targets anyone?
Improve cleanup – macrophages instead of oligos?
Reduce inflamm & scarring – steroids; chondroitinases; etc
Add guidance scaffold – Schwanns; olfactory ensheathing glia; etc
Replace growth factors – but can CNS neurons respond? gradients?
Trigger RAGs – cAMP modulators (rolipram); direct ‘gene therapy’
Rescue growth cones – calcium; microtubule stabilizers (eg taxol)
Block extrinsic inhibitors – Mabs; receptor decoys; RhoA inhibitors
Excite circuits – transmitter agonists; K+ blockers; electrical stim; etc
Replace neurons –
Remyelinate axons –
Rehabilitate!! – ESSENTIAL IN CONJUNCTION WITH ALL THE ABOVE
Stem cells
Stem cells
Stem Cells: Natural Sources
• Embryonic
• Derived from inner cell
mass of blastocyst (4-5d
post fertilization)
• Usually from excess IVFderived embryos
• NOT from aborted fetuses
(much later stage)
• Results in non-viable
embryo*
• Source for PLURIpotent stem cells
• can form tissue from endo/meso/ectoderm
• not trophoblast
• immortal/renewable
Stem Cells: Natural Sources
• Fetal
• Derived from fetal or extra-fetal tissue
• eg amniotic, umbilical cord blood, placental tissue
• does not need to disrupt fetal viability
• Few PLURIpotent cells, mostly MULTIpotent cells
• Immortal/renewable
Stem Cells: Natural Sources
• Adult
• Stem cells found within many mature tissues
• Obvious: bone marrow, skin, GI
• Not as obvious: adipose; cardiac; brain; dental pulp
• synonyms: mesenchymal stem cell; multipotent stromal cell
• MULTIpotent to OLIGOpotent
• eg hematopoietic SCs  all hematopoietic cell types
• eg neural SCs  glial and neural cells
• transdifferentiation possible, eg cardiac  neuro, etc
• Renewable
• Autologous banking
Stem Cells: Synthetic
• Somatic cell nuclear transfer
•
•
•
•
adult somatic cell nuclei + enucleated donor egg cells
Adult nucleus reprogrammed by donor egg cytoplasm
PLURIpotent
Patient-derived nuclear genes, but egg-derived
mitochondrial genes
• Used to clone animals; theoretically could be used to
clone humans
John Gurdon
Stem Cells: Synthetic
• Induced pluripotent stem cells (iPS)
• Adult somatic cells + activated “stem cell genes”
• PLURIpotent
• 100% autologous
Shinya Yamanaka
Stem Cells: Synthetic
• In vivo induced totipotent (iPS)
• Transgenic mouse + activated “stem cell genes” leads to
multiple teratomas
• TOTIpotent SCs
Stem cell uses
• Developmental studies
• How are different cell types formed?
• Patient-specific cells for in vitro drug screening
• Cell transplants
• To replace degenerated/lost tissue (neurons, cardiac, etc)
• To support local tissue with growth factors, etc
• Remember, usually need to PRE-differentiate the SCs first!
• ORGAN transplants!
• Three dimensional SC cultures now generating liver buds,
mini-brains in vitro
Stem cells: Best targets?
• Neurodegenerative diseases
• HD – one type of neuron, one site
• ALS, PD – one type of neuron, but many sites
• Alzheimer’s – Too diffuse
• Stroke
• Replace cells (many types) in affected area
• TBI; SCI
• More axonal than neuronal injury
• But likely to benefit from growth factors, remyelination
All of above will require adjunctive rehab to
properly guide graft integration and plasticity
Scientific & technical issues
• What needs to be replaced? Neurons? Glia? Axons?
• Optimal degree & type of pre-differentiation pre-transplant?
• Risks – neoplasm; rejection; procedural complications
Ethical issues
“Old days” (when embryos were the only source
for pluripotent stem cells):
• When does life begin? Are we destroying life?
Then and now:
• Human (and animal) cloning?
• Where does life begin? Are we creating life?
• Is paying women for egg donations and/or pregnancy
coercive?
• Is not paying the sources of successful cell lines unfair?
• Should stem cell treatments be sold as a commodity to
desperate patients before the risks and safeguards are
better worked out?
Stem Cells: caveat emptor
Stem cells! Get your stem cells right here!
Stem Cells: caveat emptor
Stem cells! Get your stem cells right here!
• ZERO approved indications for pluripotent stem
cells
• Hematopoietic stem cells are in use (BMT)
• “Clinics” charge exorbitant fees – for what?
• Unclear composition of cellular injections
• Tumorigenic?
• Infections?
• No systematic pre/post-care treatment plan
• No systematic follow-up for efficacy or safety
• No control treatment
Stem Cells: caveat emptor
Stem cells! Get your stem cells right here!
• ZERO approved indications for pluripotent stem
cells
• Hematopoietic stem cells are in use (BMT)
• “Clinics” charge exorbitant fees – for what?
• Unclear composition of cellular injections
• Tumorigenic?
• Infections?
• No systematic pre/post-care treatment plan
• No systematic follow-up for efficacy or safety
• No control treatment
• Difficult to dissuade individual patients/families
• More good will be done by enrolling in rigorous trials
• Great need for more innovative trial designs
Learning Objectives
1. Understand the origin and potential tissue types
created by different classes of stem cells.
2. Understand the potential benefits and risks of
stem cell applications.
3. Become versed in discussing the questions that
will frequently be raised by patients regarding
stem cells.
Further Reading
ABAD, M. ET AL. (2013) Reprogramming in vivo produces teratomas and iPS cells with
totipotency features. Nature 502:340-345.
LANCASTER, M. ET AL. (2013) Cerebral organoids model human brain development and
microcephaly. Nature 501:373-379.
LINDVALL, O. & KOKAIA, Z. (2010) Stem cells in human neurodegenerative disorders--time
for clinical translation? J Clin Invest 120:29-40.
OKITA, K. & YAMANAKA, S. (2011) Induced pluripotent stem cells: opportunities and
challenges. Philos Trans R Soc Lond B Biol Sci 366:2198-2207.
PAPPA, K. & ANAGNOU, N. (2009) Novel sources of fetal stem cells: where do they fit on
the developmental continuum? Regen Med 4:423-433.
TAKEBE, T. ET AL. (2013) Vascularized and functional human liver from an iPSC-derived
organ bud transplant. Nature 499:481-484.