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MARIE CSETE MD, PhD
CHIEF SCIENTIFIC OFFICER
[email protected]
DEGENERATIVE DISEASES
DRUG DEVELOPMENT
TRANSPLANTATION
TISSUE
ENGINEERING
TOXICICOLOGY
AGING
CANCER SURVIVAL
TRAUMA:
Spinal cord
Burns
Head injury Early Development
ALL STEM CELLS
CAN EITHER
-SELF-RENEW
and/or
-GENERATE SEVERAL
KINDS OF CELL TYPES
SELF-RENEWAL
Stem
Stem
X
Stem
X
Stem
X
Stem
Stem
Stem
X
Stem
BLOOD STEM CELLS ARE PLURIPOTENT
“-POTENCY”
• Multipotent: A few
• Pluripotent: A lot
• Totipotent: Every kind of cell including
cells of the body (somatic) and cells of
the germline (eggs, sperm)
TOTIPOTENT
• ONLY EMBRYONIC STEM CELLS ARE
CONSIDERED TOTIPOTENT
• BUT REALLY THEY ARE NOT TOTIPOTENT
BECAUSE OF THE ISSUES OF COMPLEX
ORGANIZATION
• ONLY THE FERTILIZED EGG
IS REALLY TOTIPOTENT
WHERE DO YOU GET THEM?
ADULT STEM CELLS
-ANY STAGE OF EMBRYO
-ANY STAGE OF ADULTHOOD
EMBRYONIC STEM CELLS
-BLASTOCYST EMBRYOS
-SCNT: Somatic cell nuclear transfer
-PARTHENOTES
-iPS: Induced pluripotent cells
University of Wisconsin website
University of Wisconsin, 2001.
University of Wisconsin, 2001.
University of Wisconsin, 2001.
Embryonic stem cells are derived from the inner cell mass of the
blastocyst stage embryo
. University of Wisconsin, 2001.
In the lab, trophoblast is removed and the embryonic stem cells singly
selected from the inner cell mass
University of Wisconsin, 2001.
ES cell cultivation in the laboratory:
easier with mouse than human cells
University of Wisconsin, 2001.
Using a variety of tools, in theory any cell type can be made
University of Wisconsin, 2001.
HUMAN EMBRYONIC STEM CELLS
.
EMBRYONIC
VS.
STEM CELLS
ADULT
Important differences:
• Where they come from
• Potency
• Proliferative senesence (source material
abundance)
1997—DOLLY and
THE ERA OF CLONED
ANIMALS
+
Somatic Cell Nuclear Transfer: IS NOT
HUMAN CLONING
(Remove Nucleus)
Egg Cell
(Stimulate Cell Division Process)
Inner Cell
Mass
(Pluripotent)
Blastocyst
(Fusion)
Somatic Cell nucleus (any cell in the
body other than an egg or germ cell)
(Extract Inner Cell Mass)
ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG4B.GIF
Somatic Cell Nuclear Transfer
Cultured Pluripotent
Embryonic Stem Cells
ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG3.GIF
Patient advocacy for SCNT
• No immunologic barrier with cells
generated from recipient
• Screening drugs for many common
diseases using clones from families with
inherited diseases
• First glimpse into early development
• Does not require use of embryos
Use for parthenogenetic lines
• Genetic homozygosity
• Bank cells with specific MHC proteins
• Other uses? Engineer cells for HIV
resistancemake HSC for marrow
transplantation
• SCNT AND PARTHENOGENESIS
REQUIRE AN EGG
• Human egg donation is not trivial
Functional diff
cell types
All 3 germ layers
represented
-ectoderm
-mesoderm
-endoderm
How/why would this work?
• Huge interconnectedness of protein
networks
• Changes silencing status of whole
genome: These factor awaken silenced
genes all over the chromosomes
• Ultimate test of pluripotency: Make a
whole organism
iPS lines used to make mice
Reported simultaneously
by 3 groups
-Jaenisch (MIT)
-Hochedlinger (Harvard)*
-Yamanaka (Japan)
*20% of the 121
offspring developed tumors
-viral vectors?
-not from vectors?
Hard problems
• What are network requirements for
totipotency?
• Still left with little control over
differentiation
– Transcription and environment
– Functional integration into tissue
• ES vs. cancer: Many overlapping traits
• Scale-up/manufacture: unsolved
Making ES cells easier than
controlling them: MUSCLE
Positive and negative signals
muscle
reduce
?
redox
fat
oxidize
CONTROL 2.
GUTSKINCARDIACMUSCLESKELETALMUSCLEPANCREATICBETACELLS
HEPATOCYTESNEURONSSCHWANNCELLSASTROCYTESSMOOTHMUSCLE
BONEPLATELETSREDCELLSWHITECELLSKUPFFERCELLSTENDON
Complex development
• Recapitulate the uterine environment and
signals
– Engineering interface critical
• Recapitulate the developmental course
ESdefinitive endodermforegut
endodermpancreatic endoderminsulin
producing mature beta cells
(Dr. Melissa Carpenter, NOVOCELL)
Growth cues to imitiate complex
organization of embryos
Critical issues for translation
OLIGODENDROCYTES
ASTROCYTES
?
Transplant progenitorsrisk of astrocyte scar
Transplant mature oligodendrocytesthey don’t survive transplant
Tumors and stem cells
• Common traits: Undifferentiated,
pluripotency, highly proliferative, selfrenewing, migration, common markers
• Teratomas
• Permissive environments
• Cancer stem cells are those likely to
escape treatment
• Ultimately understanding stem cells will
lead to enormous gains in cancer biology
• Chemotx wipes out stem cells?
Inner core: Slowly dividing neuroepithealial cells—
Roy et al, Nature Med 2006