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Noble, Marc
1. M. Chemiakin Redox status and progenitor cell function in development, degeneration and neoplasia Mark Noble University of Rochester Stem Cell and Regenerative Medicine Institute
2. The optimal cell for promoting neuronal survival and axonal regeneration … may not be progenitors or stem cells! O-2A progenitors Type-2 astrocytes Type-1 astrocytes GRP cells Type-2 astrocytes + BMP + BMP + CNTF
4. How do you control precursor cell function? Survival Death
5. Critical point: Small changes in redox state have big effects. The extent of redox change in this experiment is only ~15%. Mayer and Noble (1994) PNAS 91:7496-7500 Response to signaling molecules is dependent on intracellular redox state
6. Precursor cells that are reduced when isolated from the animal undergo more self-renewal in vitro. Smith et al (2000) PNAS 97:10032-10037 Oxidized Reduced Oxidized + NAC
9. Cell-extrinsic signaling molecules alter intracellular redox state in a predictable manner. Oxidized Reduced Differentiation Self-Renewal
10. Redox state modulation is a necessary component of the action of signaling molecules that alter the balance between self-renewal and differentiation
12. 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
13. Developmental maladies are diseases of precursor cells • generation of specific precursor cell populations • generation of differentiated cell types • generation of sufficient numbers of cells
15. MeHg toxicity for precursor cells and oligodendrocytes is an order of magnitude lower than reported in the literature for other cells. Astrocyte LD50=500nM O-2A progenitor cell LD50 = 25nM
17. Low levels of environmental toxicants enhance vulnerability to multiple physiological stressors
18. ERK1/2 Akt SRE PDGF receptor-α NF-kB PDGF P P P P ERK1/2 Akt SRE NF-kB P P ERK1/2 Akt SRE TrkC NF-kB NT-3 P P P P ERK1/2 Akt SRE TrkC NF-kB NT-3 P P P P PDGF receptor-α PDGF Toxicants cause loss of PDGRα but not TrkC
23. c-Cbl targets PDGFR EGFR c-Met c-Kit IGF-IR etc The redox/Fyn/c-Cbl pathway: Oxidative status converges on c-Cbl-mediated degradation of specific RTKs Li et al. (2007) PLoS Biology 5:e35 ERK1/2 Akt SRE NF-kB Fyn c-Cbl B P P P P P P ERK1/2 Akt SRE c-Cbl targeted RTK NF-kB A Receptor ligand P P P P ERK1/2 Akt SRE NF-kB Fyn c-Cbl Increased oxidative status C Ub Ub P P P P P P ERK1/2 Akt SRE NF-kB Fyn c-Cbl D P P Increased oxidative status Ub Ub Increased oxidative status Increased oxidative status
31. Increased oxidative status is seen in many diseases Alzheimer’s disease Parkinson’s disease Amyotrophic lateral sclerosis Ataxia telangiectasia Autism Multiple leukodystrophies Traumatic injuries Inflammation Chemotherapy AIDS etc, etc, etc
32. Rat neural cells Survival after BCNU treatment 0 20 40 60 80 100 120 meningioma UT-12 glioma NSC astrocytes UT-4 glioma GRP human GRP human NSC NRP O-2A/OPC Oligodendrocytes % survival Survival after cisplatin treatment 0 20 40 60 80 100 SW480 UT-12 glioma NSC UT-4 glioma meningioma human NSC astrocytes human GRP GRP NRP Oligodendrocytes O-2A/OPC % survival Human neural cells Cancer cells Normal CNS progenitor cells and oligodendrocytes are more vulnerable than cancer cells to chemotherapy Dietrich et al. (2006) J. Biology 5:22
34. Activation of c-Cbl and degradation of EGFR is blocked in GBM cells Ctrl BCNU 100 uM EGFR levels Ctrl BCNU 50 uM BCNU/ 0.5 uM PP1 Fyn kinase activity
36. The optimal cell for promoting neuronal survival and axonal regeneration … may not be progenitors or stem cells! O-2A progenitors Type-2 astrocytes Type-1 astrocytes GRP cells Type-2 astrocytes + BMP + BMP + CNTF
37. Optimizing SCI repair by pre-differentiation of specific progenitor cells into specific populations of astrocytes J. Davies et al., 2008 Journal of Biology GDA gp130 GDA BMP Lesion Control
40. Joerg Dietrich Ruolan Han Ornella Santoni Yin Miranda Yang Ana Nunes Zaibo Li Wanchang Cui Brett Stevens Hsing-Yu (Warner) Chen Christopher Folts Addie Bardin Chris Farnsworth Jun Wang Xing Qiu Erin Mahoney
42. Funding sources for work discussed NYSTEM NIH Komen Foundation for the Cure Autism Speaks Hunters Hope Department of Defense The Carlson Stem Cell Fund Ludwig Institute for Cancer Research Huntsman Cancer Institute
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
This is one approach - extrending the reach of grwoth factgor combinations
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
Want to emphasize that these are very small changes in redox state/glutathioen content that have these large effects. This suggested right away that we were dealing with a critical cellular mechanism, if it is senstiive to 15% changes
Not all precursors are the same - Look at how different these precursos are, depstie being isolated from the same animals. The cortical cells are also resistant ot inducers of differentiation and the oligodendrocytes they genearete are resistent to cell death. This work is providing us with important clues as to why different rgions of the nervous system have differnetiatl senstiityv to the same types of damage. Back to right cell for the right job - which ones do we want to transplant?
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
These receptor changes, and also reductions in cell divison, are seen in SJL mice - but not in CBA mice. To understand why this might be, we isolated O-2A progenitor cells from SJL and CBA mice and compared their vulnerability to different toxicants (with thimerosal shown here as an example). As you can see, cells from SJL mice are more vulnerable. That leads us to be interested in whether these cells are also more oxidized - and it turns out that they are. We believe that the vulnerability of SJL mice, and their cells, lies in their being intrinsically more oxidized. I will return to thimerosal in my discussion, but want to show you one more piece of data first.
Comment on programmed cell death during development
Comment on programmed cell death during development
I want to first focus on the critical impediment to the development of cancer treatments
Not all precursors are the same - Look at how different these precursos are, depstie being isolated from the same animals. The cortical cells are also resistant ot inducers of differentiation and the oligodendrocytes they genearete are resistent to cell death. This work is providing us with important clues as to why different rgions of the nervous system have differnetiatl senstiityv to the same types of damage. Back to right cell for the right job - which ones do we want to transplant?
These receptor changes, and also reductions in cell divison, are seen in SJL mice - but not in CBA mice. To understand why this might be, we isolated O-2A progenitor cells from SJL and CBA mice and compared their vulnerability to different toxicants (with thimerosal shown here as an example). As you can see, cells from SJL mice are more vulnerable. That leads us to be interested in whether these cells are also more oxidized - and it turns out that they are. We believe that the vulnerability of SJL mice, and their cells, lies in their being intrinsically more oxidized. I will return to thimerosal in my discussion, but want to show you one more piece of data first.
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
Tissue engineering without biomaterials - how common a principle is this, now that we know to look for it?
This is one approach - extrending the reach of grwoth factgor combinations
Tissue engineering without biomaterials - how common a principle is this, now that we know to look for it?
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
How do we do repair? CNS - can do harm - NSC transplants cause pain Also - as Julia said - the comparisons are difficult - this means we must identify gold standards
Let me quickly summarize this with a demosntration We’re scientists – our tools – the tools of reason are the antidote to superstition and dishonesty we can do better, and we can help teach others how to do it better – we don’t do it enough, and we, and our whole society, is paying the price As Thomas Paine, the man most responsible for conceiving the what this country might be, wrote: The most formidable weapon against errors of every kind is reason. I have never used any other, and I trust I never shall. [Thomas Paine, "Age of Reason"]
This is one approach - extrending the reach of grwoth factgor combinations
We also decided to go for something more broad-reaching it is consequences, which was to address metabolic control of cell function in genearl, and precursor cell function in particular. This is appraoched from both an empirical perspective and an evolutionary perspective
