Disorders of myelin include the hereditary leukodystrophies and cerebral palsies, as well as adult vascular, traumatic and inflammatory demyelination syndromes. To address this large and diverse group of disease, we established a cell-therapeutic approach to central remyelination, by which transplants of isolated human glial progenitor cells (GPCs) are delivered intracerebrally to neonatal recipients, which are then allowed to mature to adulthood. When the recipients are hypomyelinated mutants, such as the shiverer mouse, the transplanted cells mature largely as myelinating oligodendrocytes, and can rescue both the neurological phenotype and lifespan of the treated animals. Remarkably though, large numbers of human progenitors integrate into the recipient brains, wherein they effectively out-compete mouse progenitors, yielding mice with a substantially humanized white matter, and a major contingent of human glial progenitors - and ultimately astrocytes - in the gray matter as well. The resultant human glial-chimeric mouse brains provide us a variety of hitherto unavailable opportunities for studying human glial cells and their progenitors in vivo, including their responses to injury and disease processes that cannot be adequately modeled in vitro. In the proposed experiments, we will use these mice to assess the effects of toxic demyelination on human GPCs in vivo, so as to identify their molecular responses to injury-induced mobilization and oligodendrocytic differentiation during compensatory remyelination. In particular, we will use phenotype-specific cell sorting and gene expression analysis, to define the responses of these xenografted human GPCs to demyelination in vivo. These data, the first ever obtained specifically from human GPCs during demyelination and remyelination in vivo, should afford us fundamental new insights into the signaling events associated with remyelination, and their potentially targetable points of regulatory control. To achieve that end, we propose the following Aims:
In Aim 1, we will treat glial-chimeric mice with cuprizone so as to better understand the responses of human GPCs to demyelination, assessing their mobilization, differentiation, responses to repetitive induction, as well as their thresholds for mitotic senescence and the regulatory control thereof.
In Aim 2, we will examine the expression patterns of human GPCs in vivo, sorting them from chimeric shiverer mice both at baseline and in response to demyelination, so as to define those genes and pathways differentially regulated during GPC mobilization and remyelination.
In Aim 3 we will compare the responses of co-resident human and mouse GPCs to cuprizone demyelination, so as to identify those shared pathways likely to be high-value targets in drug development, as well as those species-specific pathways whose investigation in mice might not predict human therapeutic outcome. Together, these experiments promise to inform our efforts to define new strategies for treating demyelinating brain or spinal cord injury. In addition, the databases to be generated in the course of this work, as freely available resources to the field should prove catalytic in advancing our understanding of remyelination in vivo.
In the course of developing new human cell therapeutics for treating brain disease, we established mice in which a substantial proportion of all CNS glial cells were of human origin, especially in the white matter, the region affected in human myelin disease. In this application, we propose to use perinatal transplants of human glial progenitor cells to establish mice with largely humanized white matter, and to then subject these mice to experimental demyelination, yielding pathology similar to that of disorders such as subcortical stroke and multiple sclerosis. We will then use cell sorting techniques to separate the human glial progenitor cells from the affected mouse brains, followed by gene expression analyses to identify which genes respond to the demyelinating insult, and by what time course. By this means, we expect to define those signaling pathways involved in remyelination by normal human glial progenitor cells in vivo, knowledge that should provide us great insight into how to induce and regulate this process therapeutically.
| Khakh, Baljit S; Beaumont, Vahri; Cachope, Roger et al. (2017) Unravelling and Exploiting Astrocyte Dysfunction in Huntington's Disease. Trends Neurosci 40:422-437 |
| Windrem, Martha S; Osipovitch, Mikhail; Liu, Zhengshan et al. (2017) Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia. Cell Stem Cell 21:195-208.e6 |
| Goldman, Steven A (2017) Patience pays in spinal repair. J Clin Invest 127:3284-3286 |
| Nevin, Zachary S; Factor, Daniel C; Karl, Robert T et al. (2017) Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes. Am J Hum Genet 100:617-634 |
| Goldman, Steven A (2017) Progenitor cell-based treatment of glial disease. Prog Brain Res 231:165-189 |
| Sun, Wei; Cornwell, Adam; Li, Jiashu et al. (2017) SOX9 Is an Astrocyte-Specific Nuclear Marker in the Adult Brain Outside the Neurogenic Regions. J Neurosci 37:4493-4507 |
| Osorio, M Joana; Rowitch, David H; Tesar, Paul et al. (2017) Concise Review: Stem Cell-Based Treatment of Pelizaeus-Merzbacher Disease. Stem Cells 35:311-315 |
| Osorio, M Joana; Goldman, Steven A (2016) Glial progenitor cell-based treatment of the childhood leukodystrophies. Exp Neurol 283:476-88 |
| Goldman, Steven A (2016) Stem and Progenitor Cell-Based Therapy of the Central Nervous System: Hopes, Hype, and Wishful Thinking. Cell Stem Cell 18:174-88 |
| Nedergaard, Maiken; Goldman, Steven A (2016) BRAIN DRAIN. Sci Am 314:44-9 |
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