Stem Cell Update: Telling Hype from Hope

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Stem Cell Update Telling Hype from Hope
Ricki Lewis November 2008
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What are stem cells?
Self-renew and can differentiate.
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3 basic stem cell typesES iPS adult
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3 steps identifyisolate/extract/alteranalyze/d
eliver
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1. The gold standard human embryonic stem (hES)
cells
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Why hES cells?

• To study pathogenesis
• Drug development
• Therapeutics (cell therapy, tissue engineering)
• To compare iPS cells to -- how similar are they?

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NOT to clone humans
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hES cells from fertility clinic leftovers
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Other embryo sources

• From fertility clinics
• failed to fertilize
• early embryonic arrest
• no cleavage
• spindle defects
• aneuploid

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SCNT paved the way to iPS cells.
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2. Induced pluripotent stem (iPS) cells

• Select somatic cell
• Deliver Yamanaka factor genes
• OCT4, SOX2, KLF4, c-MYC
• Add cocktails, get desired cell types
• Use!
• Study development
• Test drugs
• Treat patient

New buzzword reprogram Old term
dedifferentiate
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Yamanaka factors Oct4 Klf4 Sox2 c-Myc
iPS cells
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iPS cells from 2 ALS patients astrocytes
(red) motor neurons (green)
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Harvard iPS Core

• ADA deficiency/SCID
• Shwachman-Bodian-Diamond syndrome
• Gaucher disease III
• Duchenne MD
• Becker MD
• Parkinson Disease
• Huntington Disease
• Type 1 diabetes
• Trisomy 21
• Lesch-Nyhan carriers

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Do iPS cells hES cells?

• Cell surfaces
• Telomerase
• Gene expression
• Yield cells from all 3 germ layers
• Normal chromosomes
• DNA profile of donor

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1rst proof of concept sickle cell disease(NEJM
2/28/08 -- iPS cells in mice)
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Potential challenges with iPS cells

• Low rate of reprogramming
• Many combos possible
• Genetic modification to alter them ( gene
  therapy)
• Teratoma
• Viral insertional mutation
• Cancer
• Transcriptome epigenetics differ for iPS and ES
• Somatic mutation

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Tailored iPS cells are just the beginning
Recapitulating organogenesis
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3. Adult Stem CellsOne source medical waste

• Horse hooves
• Cat dog testicles
• Liposuction leftovers
• Blood
• Roadkill
• Zoo deaths
• Skin after weight loss
• Fluid from knee
• Biopsies
• Extra blood vessels
• Extra brain tissue

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Extra-embryonic structures

• Membranes
• Human amniotic epithelial cells have ES cell
  markers.
• Become stem-like in culture
• Medical waste

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Umbilical cord stem cells

• Not cord blood cells
• Like mix of ES bone marrow cells
• High division rate
• Self-renewal
• No spontaneous differentiation
• Medical waste

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SHED best acronym
Stem Cells from Human Exfoliated Deciduous Teeth
Bone, cartilage, fat, mesenchyme BioEden Tooth
Cell Bank 585 89/year
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In praise of fat (Vet-Stem)
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3 applications basic research (development
disease)drug discovery/developmenttreatments
(implants, transplants, signals)
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1. Basic research progeria

• Progerin expressed in adult mesenchymal stem
  cells reveals development rerouted to favor bone
  over fat

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2. Drugs

• See origins in ES neural progenitors
• Identified glutamate pathway as mechanism of
  birth defects

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• Treatments
• Promising Pilot Studies Using Adult Stem Cells
• Batten disease
• Parkinsons disease
• ALS (many
• Epidermolysis bullosa hematopoietic)
• Toothlessness
• Chronic critical limb ischemia
• Muscular dystrophies
• Oral sub-mucosal fibrosis
• clinicaltrials.gov

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• Requirements for stem cell-based treatments
• Ethical source (opinion)
• Cells must divide in vitro
• Cryopreservation without damage
• Pluripotent
• Dont cause cancer
• Self-renewal
• Not immunogenic

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Bronchopulmonary dysplasia

• Cord pericytes
• Self-renew
• Become alveolar type II pneumocytes, which make
  surfactant yield type I, which exchange gases
  but dont divide

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Eyes a great source of stem cells
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Corneal transplants fail if no limbal cells

• In 10 years, we will have eliminated the need
  for cell therapies. If we find the signals to
  regenerate the cornea, we can deliver them in
  drops.
• Sajjad Aahmad
• Northeast England Stem Cell Institute

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RPE (Sally Temple)

• From vitrectomy cadavers (no mice)
• Normally RPE yields 6 types of retinal cells
• ES medium yields all 3 germ layers.
• Divide in culture up to 11 times.
• In clinical trials to treat Parkinsons disease.

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Cardiac not ready for prime time

• Stem cells must differentiate as smooth muscle,
  endothelium, cardiac muscle
• Must synchronize
• Lack adult K channels
• Ejection fraction improvement too little
• Could be natural recovery/healing

decellularization???
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Neural stem cells

• 1912 discovered in rodent brains, dismissed as
  artifact

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Neural Stem Cells

• 1960s -- newborn guinea pigs have stem cells near
  brain ventricles.
• Hypothesis if these mammals, born able to walk,
  need neural stem cells, so do human infants.

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1980s birds learning songs gain brain cells,
near ventricles. Have counterparts in mammalian
brain.
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Neural stem cells

• 1990s neural stem cells found in tree shrews,
  marmosets, rhesus monkeys

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Brain marrow

• 1996-1998 BrdU in brains of cancer patients
• 2001 Neural stem cells in cadavers
• 2006 Neural progenitors from epilepsy surgery

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Human neural stem cell resource

• Stem cells from different brain parts, different
  diseases
• From cadavers surgeries
• Available to researchers

http//www.nhnscr.org/ Childrens Hospital of
Orange County
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Hype !
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Proliferation of companies
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Banking cells

• Umbilical cord
• Bone marrow mesenchymal stem cells
• Future???

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Hair skin replacement

• Male pattern baldness
• Facial rejuvenation
• Leg ulcers
• Hair follicle stem cells to smooth muscle to
  vascular grafts

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Neostem very small embryonic-like stem cells
(note typo)
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Neostem spokesperson Suzanne Somers

• my own stem cells will be banked as
  bio-insurance. Now I am prepared for my future as
  the beneficiary of medical benefits while I am
  alive.

7500 to extract 750/year to store
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menstrual stem cell service
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Cellerant Therapeutics

• CLT-008 will keep people
• alive after a nuclear attack.

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For athletes, the next fountain of youth?

• NYT, 3/29/07
• MDs speculating
• No info, no news
• Banking stem cells for future injuries
• Not performance enhancement because self

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Selling hope

• Companies (most not in U.S) sell treatments that
  use
• Cord blood stem cells
• A patients own cells
• Fetal cells

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Stem cell company red flags

• No clinical trials
• Testimonials
• No follow-up
• Not done in U.S.
• PubMed no-show
• Too many claims
• Evasive or repetitive language
• Errors in basic biology

Medical Tourism
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In memory of Glenn Nichols
1950-2008
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False promises ALS

• Patients treated with the companys NurOwnTM
  therapeutic cells are expected to enjoy a rapid
  recovery and much enhanced quality of life.

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False promises

• The company is initiating a series of efficacy
  and safety studies toward a cure for ALS.
• (SOD mice on rotarod)

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A case of mistaken identity

• ALS embryonic stem cells from cell
  suspensions obtained from growth zones of
  cadaverous embryos systems and organs.

Cells from 4-8 week embryos are not hES cells.
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A look into the not-too-distant future
Signals instead of cells
For study guide www.stemcellsymphony.com
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• Stem cell activity
• Choose disease or injury
• Identify affected molecules, cells, tissues,
  organs
• Identify genes proteins
• Deliver!
• Troubleshooting
• How to not cause cancer
• How to target effects
• How to prevent adverse effects
• How to monitor response
• 6. Write an ad for your product or treatment.