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AngelaMarieLager_ETD_May2015.pdf (6.06 MB)

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Cell Reprogramming Technologies for Treatment and Understanding of Genetic Disorders of Myelin

Lager, Angela Marie
http://rave.ohiolink.edu/etdc/view?acc_num=case1427898199

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Genetics.
The oligodendrocyte lineage is essential for high-fidelity information transfer in neural circuits of the central nervous system. Oligodendrocytes arise from a pool of migratory progenitor cells that populate the brain and spinal cord shortly before birth. These oligodendrocyte progenitor cells undergo subsequent differentiation into mature oligodendrocytes, a cell whose primary function is to generate a multilayer protein-lipid membrane around axons termed myelin. Myelin segments allow saltatory conduction of action potentials down the axon, increasing impulse velocity by as much as 100-fold. Therefore, oligodendrocytes are thought to contribute to efficient signal processing in local microcircuits and are required for long-distance propagation of action potentials by projection neurons. The importance of oligodendrocytes in central nervous system function is underscored by the prevalence of neurological diseases characterized by abnormal myelination. These diseases, collectively termed leukodystrophies, encompass a spectrum of disorders associated with mutations in over 40 different oligodendrocyte lineage-specific genes. Although the genetic etiology for a majority of these disorders is well understood, less is known about how genetic abnormalities underlie cellular dysfunction and overt disease pathology. As there are currently no standard treatments for patients suffering from leukodystrophies, addressing this gap is of fundamental importance. Recent use of mouse genetic models and cell reprogramming technologies has dramatically improved our ability to understand how genetic mutations underlie disease at the molecular, cellular, and systems level. We sought to adapt these technologies to develop a method for obtaining oligodendrocyte progenitor cells—a previously inaccessible cell type. Herein, I describe our identification of oligodendrocyte lineage-specific transcription factors and their subsequent use in direct reprogramming of mouse fibroblasts to induced oligodendrocyte progenitor cells (iOPCs). iOPCs exhibit morphology and gene expression profiles similar to bona fide oligodendrocyte progenitors, can be expanded in vitro in a progenitor state capable of differentiating into mature multiprocessed oligodendrocytes, and form compact myelin when grafted into the mouse central nervous system. We have also developed a second method that allows us to direct the differentiation of oligodendrocyte progenitor cells from wild type and mutant mouse pluripotent stem cell populations. By systematically treating mouse pluripotent stem cells with small molecules and growth factors that mimic growth factor conditions observed during development, we developed a robust and rapid method for obtaining a pure population of oligodendrocyte progenitor cells. Thus, through these methods, we gain new experimental access to oligodendrocyte lineage cells for the first time. With the development of new protocols for obtaining pure populations of oligodendrocyte progenitor cells and mature oligodendrocytes, we can begin to address gaps in our basic knowledge and make technological advances in several areas: First, access to oligodendrocyte lineage cells may allow us to study regulatory programs that underlie oligodendrocyte development and acquisition of terminal identity features. Second, we may now model genetic determinants of leukodystrophies in culture to gain insight into how genetic mutations give rise to cellular dysfunction. These studies might provide a platform for drug-discovery, allowing the identification of candidate compounds that successfully modulate disease progression. Third, cell reprogramming technologies have opened the door for cell based therapies in disease management. As we can now generate oligodendrocyte progenitor cells from autologous sources, we may be able to develop personalized cell based therapies for those suffering from leukodystrophies; however, these strategies will require correction of genetic abnormalities that underlie disease. Together, our methods of obtaining oligodendrocyte progenitor cells act as a basis for future studies into treatments for patients suffering from leukodystrophies and disease understanding.
Paul Tesar, PhD (Advisor)
Ronald Conlon, PhD (Committee Chair)
Craig Hodges, PhD (Committee Member)
Warren Alilain, PhD (Committee Member)
174 p.
Developmental Biology; Genetics
myelin; oligodendrocytes; cell reprogramming; regenerative therapy; direct reprogramming; myelin repair

Recommended Citations

Citations

  • Lager, A. M. (2015). Cell Reprogramming Technologies for Treatment and Understanding of Genetic Disorders of Myelin [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1427898199

    APA Style (7th edition)

  • Lager, Angela. Cell Reprogramming Technologies for Treatment and Understanding of Genetic Disorders of Myelin. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1427898199.

    MLA Style (8th edition)

  • Lager, Angela. "Cell Reprogramming Technologies for Treatment and Understanding of Genetic Disorders of Myelin." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1427898199

    Chicago Manual of Style (17th edition)

case1427898199
445
© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.