title: iPS-derived neural progenitor cells from PPMS patients reveal defect in myelin injury response.
abstract: Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system (CNS) currently lacking any effective treatment. Promoting endogenous brain repair offers a potential strategy to halt and possibly restore neurologic function in PPMS. To understand how the microenvironment within white matter lesions plays a role in repair we have focused on neural progenitor cells (NPCs) since these are found in lesions in PPMS and have been found to influence oligodendrocyte progenitor cell maturation (OPCs). To better understand the cellular nature of NPCs in PPMS we developed iPS cells from blood samples of PPMS patients and age matched non-disease spouse or blood relative controls. Using these iPS cell lines we determined that the NPCs from PPMS cases provided no neuroprotection against active CNS demyelination compared to NPCs from control iPS lines which were capable of completely preventing injury. Conditioned media (CM) from PPMS NPCs provides no protection to OPCs and prevents maturation of OPCs into oligodendrocytes in vitro. We also found that CM from PPMS iPS NPCs elicited patient-specific differences in the response to compounds that should foster oligodendrocyte (OL) maturation. Together, these data establish a new model for understanding the nature of myelination defects in PPMS which may lead to novel targeted approaches for preventing demyelination in these patients.
authors.affiliation: Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Nicaise
authors.affiliation: Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: Banda
authors.affiliation: Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States; Stem Cell Institute, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Guzzo
authors.affiliation: Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States.
authors.forename: Kristen
authors.initials: K
authors.lastname: Russomanno
authors.affiliation: Neurology, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States.
authors.forename: Wanda
authors.initials: W
authors.lastname: Castro-Borrero
authors.affiliation: Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Willis
authors.affiliation: Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States.
authors.forename: Kasey M
authors.initials: KM
authors.lastname: Johnson
authors.affiliation: The Mandell Center for Multiple Sclerosis, Mount Sinai Rehabilitation Hospital, Hartford, CT 06112, United States.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Lo
authors.affiliation: Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States; Stem Cell Institute, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06032, United States. Electronic address: crocker@uchc.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Crocker
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D002454:Cell Differentiation / Q000187:drug effects; D002974:Clemastine / Q000494:pharmacology / Q000627:therapeutic use; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003471:Cuprizone / Q000633:toxicity; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000737:chemistry / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008810:Mice, Inbred C57BL; D008825:Miconazole / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity; D020528:Multiple Sclerosis, Chronic Progressive / Q000139:chemically induced / Q000473:pathology*; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000473:pathology* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure
chemical_list: D017077:Culture Media, Conditioned; C499047:Mbp protein, mouse; D008996:Monoamine Oxidase Inhibitors; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D003471:Cuprizone; D008825:Miconazole; D002974:Clemastine
keywords: Induced pluripotent stem cells; Neural progenitor cells; Oligodendrocytes; Primary progressive multiple sclerosis