Apidays New York 2024 - The Good, the Bad and the Governed by David O'Neill, ...
Rowitch, David
1. OLIGODENDROCYTES IN CNS DEVELOPMENT, DISEASE AND MYELIN REGENERATION David Rowitch, MD, PhD Departments of Pediatrics and Neurosurgery Howard Hughes Medical Institute UCSF
5. Franklin and ffrench-Constant, 2008, Nat. Neurosci. Rev. Two outcomes of MS lesions Repair Chronic demyelination MS progression comprises (1) Autoimmune attack on OL, (2) inability to effectively repair in timely manner
6. OLIG1/2 in CNS Development and Disease Lu et al., 2000, Neuron ; Zhou et al., 2000, Neuron ; Lu et al., 2002, Cell ; Zhou and Anderson, 2002; Cell; Takebayashi et al., 2002, Curr. Biol. ; Ligon, Huillard et al., 2007, Neuron; Arnett, Fancy et al., 2004, Science; Sun et al., 20111, Neuron ; Mehta et al., 2011, Cancer Cell Richard Lu (UTSW) Chuck Stiles (DFCI) Heather Arnett (Amgen) Steve Fancy (UCSF) Robin Franklin (Cambridge) Embryonic Neural Tube
7. OLIG1 expression in multiple sclerosis Olig1 nuclear Olig1 cytoplasmic Unaffected white matter Edge MS plaque Arnett, Fancy et al., 2004, Science
8. Demyelinated axons OLP Focal area of OL death: demyelination Myelinated tissue Lysolethicin gliotoxic injury model Remyelination Focal lysolecithin injection (Solochome cyanine)
9. Olig1 is required for remyelination Focal lysolecithin injection (Solochome cyanine) Arnett, Fancy et al., 2004, Science Olig1 -/- Wild-type 14 dpl 28 dpl Ultra structure
10. Developmental perspective Chronic demyelination “ Blocked” OLP are present in human MS lesions NG2 PDGFR Pre-OL OLP OL Olig2 NG2 Olig1 (Nuclear) PLP Olig1 (Cytoplasmic) APC (CC1) O4 Nkx2.2 O1 APC Axin2 Are OLP blocked in MS?
20. Huang et al., 2009, Nature Axin2 required to inhibit Wnt pathway
21. XAV939 stabilizes Axin2 in OLP in vitro Huang et al., 2009, Nature Fancy et al., Nature Neuroscience, In press
22. Add XAV939 small molecule Wnt inhibitor… Wnt inhibitor accelerates remyelination Fancy et al., Nature Neuroscience, In press OLP differentiation and remyelination accelerated ~4 days (Axin2-/- mice unaffected by XAV)
23. XAV939 does not affect inflammatory, gliotic response, OL death, OLP recruitment or proliferation Wnt inhibitor accelerates remyelination
25. NSC Replacement NSC Regulation Perspective on neural progenitor transplant versus regulation Pre-OL OLP OL MS
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28. Restricted origins, diffuse migration and transplant of oligodendrocytes Pringle et al., 1993 Neuron ; Orentas et al., 1999 Development ; Rowitch, 2004 Nat. Neurosci. Rev. ; Windrem et al., 2008 Cell Stem Cell Human OL in Shi mouse brain. Work of Goldman lab, U. Rochester.
32. Acknowledgements Steve Fancy Vivi Heine Emily Harrington Tracy Yuen John Silberis Jose Otero Eric Huang David Rowitch UCSF Richard Lu (UTSW) Heather Arnett (Amgen) Charles Stiles Dana-Farber Cancer Institute Chao Zhao Robin Franklin Cambridge University Saraid Billards Hannah Kenney Children ’s Hospital, Boston Stephen Huhn Stem Cells, Inc. Roel Nusse Stanford University