Stem cells and neuroscience: Biology, applications, and

controversy

Noam Y. Harel, MD, PhD12 November 2013Brain 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 Objectives1. 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.

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 – Stem cells

Remyelinate axons – Stem cells

Rehabilitate!!

Strategery: Repair and RecoveryTargets anyone?

– ESSENTIAL IN CONJUNCTION WITH ALL THE ABOVE

• Embryonic• Derived from inner cell

mass of blastocyst (4-5d post fertilization) • Usually from excess IVF-

derived 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: Natural Sources

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

• Induced pluripotent stem cells (iPS)• Adult somatic cells + activated “stem cell genes”• PLURIpotent• 100% autologous

Stem Cells: Synthetic

Shinya Yamanaka

• In vivo induced totipotent (iPS)• Transgenic mouse + activated “stem cell genes” leads to

multiple teratomas• TOTIpotent SCs

Stem Cells: Synthetic

• 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 cell uses

• 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

Stem cells: Best targets?

• What needs to be replaced? Neurons? Glia? Axons?

• Optimal degree & type of pre-differentiation pre-transplant?

• Risks – neoplasm; rejection; procedural complications

Scientific & technical 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?

Ethical issues

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

Stem Cells: caveat emptor

Learning Objectives1. 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.

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.

Further Reading