Transcript Potential uses for stem cells

Stem cells: The present,
and the promise.
Tim McCaffrey, Ph.D.
Professor of Biochemistry and Molecular Biology
Director, The Catherine Birch McCormick Genomics Center
Potential uses for stem cells
Aging?
Diabetes?
Skin?
Making embryonic stem cells
Sources of stem cells
Uses for
cord blood
Malignant Diseases
* Acute lymphocytic leukemia
* Acute myelocytic leukemia
* Juvenile chronic myelogenous
leukemia
* Chronic myelogenous leukemia
* Neuroblastoma
* Refractory anemia with blasts
Nonmalignant Diseases
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Fanconi anemia
Aplastic anemia
Refractory anemia
Thalassemia
Sickle cell anemia
Amegakaryocytic thrombocytopenia
Kostmann syndrome
Blackfan-Diamond syndrome
Severe combined immunodeficiency
X-linked lymphoproliferative disorder
Wiskott-Aldrich syndrome
Hurler syndrome
Hunter syndrome
Gunther disease
Osteopetrosis
Globoid cell leukodystrophy
Adrenoleukodystrophy
Lesch-Nyhan syndrome
Marrow repopulation w/ stem cells
Causes of Death.
United States. 1997.
% of Deaths
All causes
1 Diseases of heart
100.0
31.4
3 Cerebrovascular diseases
6.9
15 Atherosclerosis
0.7
Combined cardiovascular deaths-->
2 Malignant neoplasms (all cancers)
39.0
23.3
4 Chronic obstructive pulmonary diseases
4.7
5 Accidents and adverse effects
4.1
6 Pneumonia and influenza
3.7
7 Diabetes mellitus
2.7
8 Suicide
1.3
14 Human immunodeficiency virus infection
0.7
. . . All other causes . . . . . . . .
National Vital Statistics Reports, Vol. 47, No. 19, June 30, 1999
15.4
Age and Cardiovascular Disease
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Source: World Health Organization Autopsy Study, 1976.
Efficacy of Angioplasty for Dilating Blockage
Textbook of Medicine, 2nd edition.
Surviving Myocardial Infarction
Half of all myocardial infarctions are fatal.
However, if ER care is available, mortality is less than 12%.
Because of
1) angioplasty and
2) thrombolytics (tPA, streptokinase) clot-busters
3) aspirin
4) aggressive and new anticoagulants
More people are surviving MI.
MI and cardiomyocyte damage
Strategies for cardiac repair
- Simple cardiomyoplasty - - reduce the dilation surgically
- Angiogenic therapy - - induce new blood muscle formation
- Laser-based reperfusion -- PMR/TMR
- Cardiac regeneration --- IDEAL
- Cardiac stem cell therapy --- the next best thing
Stem
cell therapy- Goals
• Restore blood flood to the ischemic region
--> angiogenesis alone is not enough
• Replace or regenerate fused and coupled cardiomyocytes
• Prevent inflammatory process
• Prevent fibroproliferative stiffening
• Increase cardiac performance, thus, quality of life
• Survival, survival, survival
Types of stem cells tested
Embryonic stem cells
-cardiomyocyte progenitors (beating)
Adult stem cells
- skeletal muscle progenitors, satellite cells
- hematopoetic stem cells (bone marrow derived)
- mobilized hematopoetic stem cells (endogenous)
- liver stem cells
- mesenchymal stem cells
Embryoid body cardiomyocytes
As few as several
hundred embryonic
stem cells will
spontaneously
aggregate.
Within hours they
will polarize and
spontaneously
contracting heart
‘beats’ are visible.
Problems with ES therapy
• ethical issues of destroying human embryos
• legal limitations prevent Federal funds to create new lines
• probability of immune rejection is high
• almost no ability to control their differentiation completely
• possibility of teratocarcinoma is very real
• viral and bacterial contamination of long-lived cultures
(particularly with mouse feeder layer, bovine serum)
• proven genetic deterioration of the cells
• if you can’t sell Vioxx, how do you ‘sell’ cells?
Adult stem cells
Advantages:
- almost certainly no rejection issues
- no destruction of embryonic/fetal tissues
- should be plentiful and renewable
- might allow identification of myogenic factor
Disadvantages:
- currently, yield is low, so ‘mobilization’ is used
- possible introduction of neo-antigens
- controlling differentiation is now minimal
- ??? Telomeric barriers ???
- market uncertainty “Where’s the drug?”
Biosense/NOGA (Cordis)
GPS for the heart
 Catheter tip is both an ECG
electrode and a GPS antenae
 Tip placement is controled by
user under direction of computer
mapping routine.
 As new data points are
gathered, the computer constructs
a map from interpolation.
Voltage Map of the Left Ventricle
25 mV
Biosense can
combine
electrical
activity with
wall motion at
each point.
5 mV
1.0 cm
NOGA-based delivery of stem cells
Satellite cell cardiomyoplasty
(Blue nuclei = host heart;
Red = donor skeletal satellite cells)
SPECT and NOGA
Before
After
Reversible
Irreversible
Injection
Sites
2 months
post-op
15 injections
of auto.
bone marrow
monocytes
Questions for stem cell therapy
• Is the damaging factor (virus, autoimmunity) gone?
• What is the right replacement cell (s)?
• What is right timing for transplantation?
• How to keep the cells at the infarct site?
• Will healthy cells prevent disease progression?
• Will healthy myocytes couple and entrain?
• BIG QUESTION: Where are the cells?
• BIGGER QUESTION: Will it work in old people?
Real-time imaging of
fluorescently tagged cells
MetaMouse: epifluorescent cell detection
New Options for Producing
Embryonic Stem Cells
• Non-destructive sampling of blastocysts.
• Identify non-viable blastocysts for ES production.
• “Retrodifferentiation” of adult cells to stem cells.
Blastomere-derived ES cells.
Production of ES lines without destroying embryos.
From Klimanskaya, Lanza (Advanced Cell Technologies) Nature. 2006 Jan 12;439(7073):216-9.
Full differentiation of blast-ES
Blast ES implanted into kidney capsule of immunodeficient mouse.
Neural
(ectodermal)
Smooth muscle
(mesodermal)
Intestinal
(endodermal)
From Klimanskaya, Lanza (Advanced Cell Technologies) Nature. 2006 Jan 12;439(7073):216-9.
ES cells from stalled fertilizations
Naturally dead embryos yield stem cells-'Stalled' embryos could be new source of
cell lines.
Stojkovic et al. Stem Cells: Published online: 21
September 2006;
Of 13 embryos naturally arrested at 6-7 post-fertilization,
1 embryonic stem cell line could be established.
Summary:
• Both embryonic and adult stem cells have limitless
scientific potential.
• Adult stem cells probably have greater immediate
therapeutic value.
• Embryonic stem cells probably can be created without
destroying viable embryos.
• Therapeutically, probably stem-cell derived factors will be
used to promote tissue regeneration from resident stem cells.