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CANCER SURVIVAL
Early Development
DRUG DEVELOPMENT
TOXICICOLOGY
TRANSPLANTATIONDEGENERATIVE DISEASES
TRAUMA:Spinal cordBurnsHead injury
AGING
TISSUEENGINEERING
ALL STEM CELLS
CAN EITHER
-SELF-RENEW
and/or
-GENERATE SEVERALKINDS OF CELL TYPES
SELF-RENEWAL
Stem Stem
StemStem Stem
Stem Stem
X
XX
StemX
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.
. 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
HUMAN EMBRYONIC STEM CELLS
.
• Where they come from• Potency• Proliferative senesence (source material
abundance)
EMBRYONIC VS. ADULT STEM CELLS
Important differences:
1997—DOLLY andTHE ERA OF CLONEDANIMALS
+
ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG4B.GIF
Blastocyst
Inner Cell Mass(Pluripotent)
Egg Cell (Remove Nucleus)
(Fusion)
Somatic Cell Nuclear Transfer
(Extract Inner Cell Mass)
Cultured PluripotentEmbryonic Stem Cells
Somatic Cell Nuclear Transfer: IS NOT HUMAN CLONING
Somatic Cell nucleus (any cell in the body other than an egg or germ cell)
(Stimulate Cell Division Process)
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 resistancemake HSC for marrow transplantation
• SCNT AND PARTHENOGENESIS REQUIRE AN EGG
• Human egg donation is not trivial
All 3 germ layersrepresented-ectoderm-mesoderm-endoderm
Functional diffcell types
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 simultaneouslyby 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
?muscle fat
Positive and negative signals
redoxreduce oxidize
CONTROL 2.
GUTSKINCARDIACMUSCLESKELETALMUSCLEPANCREATICBETACELLSHEPATOCYTESNEURONSSCHWANNCELLSASTROCYTESSMOOTHMUSCLEBONEPLATELETSREDCELLSWHITECELLSKUPFFERCELLSTENDON
Complex development
• Recapitulate the uterine environment and signals– Engineering interface critical
• Recapitulate the developmental course
ESdefinitive endodermforegut endodermpancreatic endoderminsulin producing mature beta cells
(Dr. Melissa Carpenter, NOVOCELL)
Growth cues to imitiate complex organization of embryos
Critical issues for translation
OLIGODENDROCYTES ASTROCYTES
?Transplant progenitorsrisk of astrocyte scarTransplant mature oligodendrocytesthey don’t survive transplant
Tumors and stem cells• Common traits: Undifferentiated, pluripotency, highly
proliferative, self-renewing, 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
