asymmetric self-renewal by distributed stem cells: misunderstood in the past, important for the...
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Asymmetric Self-RenewalAsymmetric Self-RenewalBy Distributed Stem Cells:By Distributed Stem Cells:
Misunderstood in the Past, Important for the FutureMisunderstood in the Past, Important for the Future
James L. Sherley, M.D., Ph.D.James L. Sherley, M.D., Ph.D.DirectorDirector
The Adult Stem Cell Technology Center, LLCThe Adult Stem Cell Technology Center, LLCBoston, MA, USABoston, MA, USA
ASCTC
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Fetal, Neonatal, AdultFetal, Neonatal, AdultDevelopmentDevelopment
EarlyEarlyEmbryonicEmbryonicDevelopmentDevelopment
Fetal SCsFetal SCsGermline SCsGermline SCsPost-natal SCsPost-natal SCsSomatic SCsSomatic SCsTissue SCsTissue SCsAdult SCsAdult SCs
EpiblastsEpiblasts[embryonic SCs][embryonic SCs]EmbryonicEmbryonic precursorsprecursors
EmbryonicEmbryonic
Post-EmbryonicPost-Embryonic
Sources of Stem CellsSources of Stem Cells(SCs) During(SCs) During
Mammalian DevelopmentMammalian Development
Distributed Stem Cells?Distributed Stem Cells?(DSCs)(DSCs)
Fetal SCsFetal SCsGermline SCsGermline SCsPost-natal SCsPost-natal SCsSomatic SCsSomatic SCsTissue SCsTissue SCsAdult SCsAdult SCs
EmbryonicEmbryonic
Post-EmbryonicPost-Embryonic““DISTRIBUTED STEM CELLS”DISTRIBUTED STEM CELLS”DSCsDSCs
(Sherley, 2008,(Sherley, 2008,Breast DiseaseBreast Disease 2929, 37-46), 37-46)
For For DistributedDistributed Potency Potency
Asymmetric Self-RenewalAsymmetric Self-RenewalIn vivo and in vitroIn vivo and in vitro
Embryonic stem cellsEmbryonic stem cellsPrimordial germ cellsPrimordial germ cells
Induced pluripotent SCsInduced pluripotent SCsSymmetric Self-RenewalSymmetric Self-Renewal
In vitro In vitro
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The Pervasive Stem Cell Definition:The Pervasive Stem Cell Definition:
Self-renewaSelf-renewal or l or DifferentiationDifferentiation
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SymmetricSymmetricSelf-renewal Self-renewal
The Pervasive Stem Cell Definition:The Pervasive Stem Cell Definition:
Self-renewaSelf-renewal or l or DifferentiationDifferentiation
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SymmetricSymmetricSelf-renewal Self-renewal
An Inadequate Definition For Distributed Stem CellsAn Inadequate Definition For Distributed Stem Cells
A Gnomonic for Distributed Stem Cells:A Gnomonic for Distributed Stem Cells:
Self-renewaSelf-renewal AND l AND DifferentiationDifferentiation,,continuously and simultaneouslycontinuously and simultaneously
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““AsymmetricAsymmetricSelf-renewal” Self-renewal”
Tissue Cell TurnoverTissue Cell TurnoverThe mark of distributedThe mark of distributed
stem cells (DSCs):stem cells (DSCs):Asymmetric Self-RenewalAsymmetric Self-Renewal
Potten Potten et alet al., 2003., 2003
DeathDeath
TerminalTerminalArrestArrest
DifferentiationDifferentiation
SymmetricSymmetricKineticsKinetics
AsymmetricAsymmetricSelf-renewalSelf-renewalCell KineticsCell Kinetics
DSC (DSC (niche)niche)
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A CENTRAL QUESTION:A CENTRAL QUESTION:
What is the cell kinetics form ofWhat is the cell kinetics form ofasymmetric self-renewal?asymmetric self-renewal?
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Mathematical Identity, butMathematical Identity, but
Biological DistinctionsBiological Distinctions
pp1-p1-p
StochasticStochastic
vs.vs.
DeterminedDetermined
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Biological DistinctionsBiological Distinctions
StochasticStochastic1.1. Extinction probabilityExtinction probability2.2. Mutation accrualMutation accrual
DeterminedDetermined1.1. No DSC differentiationNo DSC differentiation2.2. Individual asymmetric divisionIndividual asymmetric division3.3. Mutation avoidance?Mutation avoidance?4.4. Unique cellular programs!Unique cellular programs!
pp1-p1-p vs.vs.
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≠≠
Developmental Asymmetric Divisions Are NotDevelopmental Asymmetric Divisions Are NotEquivalent to Asymmetric Self-Renewal DivisionsEquivalent to Asymmetric Self-Renewal Divisions
Asymmetric DivisionAsymmetric Division• Sisters unequalSisters unequal• Both sisters differBoth sisters differ from parentfrom parent• LimitedLimited
Asymmetric Self-RenewalAsymmetric Self-Renewal• Sisters unequalSisters unequal• One sister equalOne sister equal to parentto parent• Continuous over lifespanContinuous over lifespan
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Biological DistinctionsBiological Distinctions
StochasticStochastic1.1. Extinction probabilityExtinction probability2.2. Mutation accrualMutation accrual
DeterminedDetermined1.1. No DSC differentiationNo DSC differentiation2.2. Individual asymmetric divisionIndividual asymmetric division3.3. Mutation avoidance?Mutation avoidance?4.4. Unique cellular programs!Unique cellular programs!
pp1-p1-p vs.vs.
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Asymmetric Self-Renewal Associated (ASRA)Asymmetric Self-Renewal Associated (ASRA)Genes: Highly Specific Biomarkers for DSCsGenes: Highly Specific Biomarkers for DSCs
SYMSYM
ASYMASYM
[Noh [Noh et al.et al. 2011, 2011, PLoS ONEPLoS ONE]]
SYMSYM ASYMASYM
CyA
CyA
CX
CR
6C
XC
R6
DN
AD
NA
Pha
seP
hase
[Taghizadeh [Taghizadeh et alet al., 2010,., 2010, PLoS ONE PLoS ONE]] ASCTC
Stem CellStem CellTherapyTherapy
““Adult” Stem Cells (Adult” Stem Cells (DSCsDSCs))Embryonic Stem Cells (Embryonic Stem Cells (ESCsESCs))
Induced Pluripotent Stem Cells (Induced Pluripotent Stem Cells (iPSCsiPSCs))
Proposed Stem Cells for Tissue Replacement Proposed Stem Cells for Tissue Replacement
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StochasticStochastic
DeterministicDeterministic
(In Vitro)(In Vitro)Self-RenewalSelf-Renewal
OROR Differentiation Differentiation
Stemness PreservedStemness Preserved““AsymmetricAsymmetricSelf-Renewal”Self-Renewal”
Embryonic and iP Stem CellsEmbryonic and iP Stem Cells
Distributed Stem CellsDistributed Stem Cells
Mathematical Features of Cell Production with DifferentiationMathematical Features of Cell Production with Differentiation
pp1-p1-p
a
b
d
c
Self-RenewalSelf-Renewal
ANDAND Differentiation Differentiation
Loss of Loss of StemnessStemness
a
a
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Stem CellStem CellTherapyTherapy
““Adult” Stem Cells (Adult” Stem Cells (DSCsDSCs))Embryonic Stem Cells (Embryonic Stem Cells (ESCsESCs))
Induced Pluripotent Stem Cells (Induced Pluripotent Stem Cells (iPSCsiPSCs))
Proposed Stem Cells for Tissue Replacement Proposed Stem Cells for Tissue Replacement
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NormalNormalTissueTissue
Damaged or DiseasedDamaged or DiseasedTissueTissue
Tissue Therapy with ESCs and iPSCs?Tissue Therapy with ESCs and iPSCs?
REPAIR?REPAIR?
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NormalNormalTissueTissue
Damaged or DiseasedDamaged or DiseasedTissueTissue
Short-livedShort-livedRepair!!!!Repair!!!!
(Tumors!)(Tumors!)
Tissue Therapy with ESCs and iPSCsTissue Therapy with ESCs and iPSCs
hESCs and iPSCshESCs and iPSCs- ethical issues (hESCs)- ethical issues (hESCs)- epigenetic defects- epigenetic defects- genetic defects- genetic defects
PurificationPurification- ESCs!- ESCs!- iPSCs!- iPSCs!- other differentiated cells- other differentiated cells
““DevelopDevelopIn VitroIn Vitro”” Differentiated Cells (Immature)Differentiated Cells (Immature)
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NormalNormalTissueTissue
Damaged or DiseasedDamaged or DiseasedTissueTissue
DSC ExpansionDSC Expansionisis possible! possible!
• AutologousAutologous• AllogeneicAllogeneic• Informed ConsentInformed Consent
RenewingRenewingRepairedRepaired
TissueTissue
Tissue Therapy with Distributed Stem CellsTissue Therapy with Distributed Stem Cells
- purity not required- purity not required- expansion not always- expansion not always criticalcritical
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NormalNormalTissueTissue
Damaged or DiseasedDamaged or DiseasedTissueTissue
An DSC Bottleneck for Tissue TherapyAn DSC Bottleneck for Tissue Therapy
““DevelopDevelopIn VitroIn Vitro””
Isolate, stabilize, expandIsolate, stabilize, expand
Distributed Stem CellsDistributed Stem Cells
RepairedRepairedTissue?Tissue?
Tumor RiskTumor RiskRemainsRemains
[Sherley, J. L. 2004, [Sherley, J. L. 2004, J. Biomed. BiotechJ. Biomed. Biotech. 2, 71-72.]. 2, 71-72.]Differentiated Cells (Immature)Differentiated Cells (Immature)
hESCs and iPSCshESCs and iPSCs- ethical issues (hESCs)- ethical issues (hESCs)- epigenetic defects- epigenetic defects- genetic defects- genetic defects
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Distributed Stem Cell Distributed Stem Cell Asymmetric Self-RenewalAsymmetric Self-Renewal
Embryonic developmentEmbryonic development
hESCshESCs ??iPSCsiPSCs
Immature?Immature?
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Distributed Stem Cell Distributed Stem Cell Asymmetric Self-RenewalAsymmetric Self-Renewal
Embryonic developmentEmbryonic development
hESCshESCs ??iPSCsiPSCs
Xanthine (p53-KO mimic)Xanthine (p53-KO mimic)
Immature?Immature?
Pare & Sherley, 2011, Pare & Sherley, 2011, J. Biomed. Biotech.J. Biomed. Biotech.
New Patent: USPTO No. 8,759,098, June 24, 2014New Patent: USPTO No. 8,759,098, June 24, 2014
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DiseaseDiseaseResearchResearch
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