title: Human iPSC-Derived Immature Astroglia Promote Oligodendrogenesis by Increasing TIMP-1 Secretion.
abstract: Astrocytes, once considered passive support cells, are increasingly appreciated as dynamic regulators of neuronal development and function, in part via secreted factors. The extent to which they similarly regulate oligodendrocytes or proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) is less understood. Here, we generated astrocytes from human pluripotent stem cells (hiPSC-Astros) and demonstrated that immature astrocytes, as opposed to mature ones, promote oligodendrogenesis in vitro. In the PVL mouse model of neonatal hypoxic/ischemic encephalopathy, associated with cerebral palsy in humans, transplanted immature hiPSC-Astros promoted myelinogenesis and behavioral outcome. We further identified TIMP-1 as a selectively upregulated component secreted from immature hiPSC-Astros. Accordingly, in the rat PVL model, intranasal administration of conditioned medium from immature hiPSC-Astros promoted oligodendrocyte maturation in a TIMP-1-dependent manner. Our findings suggest stage-specific developmental interactions between astroglia and oligodendroglia and have important therapeutic implications for promoting myelinogenesis.
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, and Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA. Electronic address: peng.jiang@unmc.edu.
authors.forename: Peng
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA; Center for Neuroscience, School of Medicine, University of California at Davis, Davis, CA 95618, USA.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA; Center for Neuroscience, School of Medicine, University of California at Davis, Davis, CA 95618, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Pleasure
authors.affiliation: Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA; Center for Neuroscience, School of Medicine, University of California at Davis, Davis, CA 95618, USA. Electronic address: wbdeng@ucdavis.edu.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Deng
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007969:Leukomalacia, Periventricular / Q000473:pathology / Q000628:therapy; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000378:metabolism / Q000648:ultrastructure; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1
keywords: human induced pluripotent stem cells; immature astrocytes; myelination; oligodendrocytes; periventricular leukomalacia