Redox Biology, Stem Cell Biology and Autism

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Redox Biology, Stem Cell Biology and Autism Mark
Noble University of Rochester Stem Cell and
Regenerative Medicine Institute
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To cause change, learn how to be a trimtab!
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Understanding Avalanches Relevance to Injury
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Understanding Avalanches Relevance to Injury
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Understanding Avalanches Relevance to Injury
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Understanding Avalanches Relevance to Injury
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Treating Autism - What stage of the
avalanche? Are there multiple stages occurring at
the same time? What are the implications both
for the types of interventions and for the length
of time over which interventions might be
expected to yield benefit?
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The importance of resilience theory
Clear Lake
Algal overgrowth
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Algal overgrowth
Clear Lake
Phosphate Concentration
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Regressive autism A case of resilience
failed? What is the underlying biology of sudden
changes in developmental trajectory?
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Is regressive autism a cumulative effect of
multiple small changes?
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All disease is based on cellular dysfunction
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Adult O-2A/OPCs
Noble et al. Dev. Biol. (2004) 26533-52
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Developmental maladies are diseases of precursor
cells

• generation of specific precursor cell
  populations
• generation of differentiated cell types
• generation of sufficient numbers of cells

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Autism may be caused, at least in part, by
disruption of normal stem and progenitor cell
function. But beware of the predators! This does
not mean autism is amenable to stem cell
therapies. At present, there is no basis for
proposing the use of stem cell therapies for
autism, no knowledge about what one is trying to
repair, no information about what cells would be
relevant, etc.
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The biology of astrogliosis Lessons from the
study of spinal cord injury on role of different
astrocyte populations in normal and abnormal CNS
function
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Transplant of GRP-derived astrocytes in SCI
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Whats critical? Is it the precursor cell or
the astrocyte?
GRP cell
BMP
CNTF, LIF, IL-6
GDABMP
GDAgp130
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Which astrocytes are in the brains of autistic
children? What are the implications of this
question?
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Redox state as a modulator of cell function
Redox state The balance between reducing and
oxidizing equivalents. Electron transfer
bioenergetics Not all oxidation is oxidative
stress
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Antioxidants protect against cell death
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Small changes in redox state can have large
effects on cell function Critical point The
extent of redox change is only 15.
Mayer and Noble (2004) PNAS 917496-7500
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Redox state also controls precursor cell
function Precursor cells that are more reduced
when isolated from the animal undergo more
self-renewal in vitro.
Smith et al (2000) PNAS 9710032-10037
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Cell-extrinsic signaling molecules alter
intracellular redox state in a predictable manner.
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• Redox state controls precursor cell function.
• Classical signaling molecules that enhance
  self-renewal or induce differentiation alter
  redox state as a necessary component of their
  mechanism.
• The organism uses developmental (genetic)
  regulation of redox state to control precursor
  cell function.

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Do redox abnormalities create a vulnerability
phenotype? If so, what are the implications?
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Redox state and control of the immune response
Oxidized macrophages promote a Th2 response.
Would this contribute to the production of
inflammatory cytokines that promote scarring in
the central nervous system?
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The challenge of toxicology
World Health Organization estimates 30-40 of the
burden of childhood disease is due to
environmental factors There are 80-150 thousand
registered chemicals for which we have no
information - which means they are unregulated
(an assumption of safety) We each have hundreds
of these chemicals in our bodies - and we know
nothing about combined activities
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Many environmental toxicants are potent
pro-oxidants
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MeHg toxicity for precursor cells and
oligodendrocytes is an order of magnitude lower
than reported in the literature for other cells.
LD50500nM
MTT Survival Curves
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Low concentrations of MeHg causes O-2A
progenitors to become more oxidized
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Low concentrations of MeHg inhibit O-2A
progenitor cell division
Control
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Low levels of toxicants can enhance vulnerability
to other physiological stressors
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Oxidative status converges on c-Cbl mediated
degradation of specific RTKs
Small increases in oxidative status
Fyn
C-Cbl
EGFR
c-Met
Li et al. (2007) PLoS Biology 5e35
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Thimerosal Its not special - in either
direction.
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What to do next The individual
Early intervention Should more attention be paid
to the use of sign language? Is metabolic
regulation critical? Is overcoming gliosis
critical? Understanding the vulnerability
phenotype (genetics, diet, exposure to
toxicants) Understanding the avalanche - the
nature of resilience Resilience, toxicology and
regressive autism Regressive autism vs
early-onset autism Protection from the predators
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What do to next Society
Data. Data. Data. (e.g., chelation, therapeutic
approaches) The need for informative
epidemiology How much of the increase is
biological? What do changes in diagnosis mean
for evaluating contributions of toxicants? Costs
to society The need for trim-tabbing
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