Images from Windrem et al., 2008 ( A-B) Goldman et al., 2012 ( C-D) Windrem et al., 2004 ( E) figure adapted from (Osorio and Goldman, 2016a).Ī, hGPCs neonatally transplanted into either congenitally hypomyelinated shiverer × rag2 −/− ( left column), or into normally myelinated rag2 −/− ( right) mouse brain, disperse and expand broadly throughout the brain as a function of age. Electron micrograph of a 16-week-old shiverer mouse implanted perinatally with hGPCs, shows a shiverer axon with a densely compacted myelin sheath. Untransplanted shiverer brains do not have organized nodes of Ranvier and, hence, cannot support saltatory conduction (Caspr, red Kv1.2, green) E. D, Reconstituted nodes of Ranvier in the cervical spinal cord of a transplanted and rescued 1-year-old shi/shi × rag2−/− mouse, showing paranodal Caspr protein and juxtaparanodal potassium channel Kv1.2, symmetrically flanking each node. All cells were stained with DAPI ( blue) donor cells were identified by human nuclear antigen (hN, red), and donor–derived myelin by MBP ( green). C, Sagittal view through cerebellum of a year-old engrafted shi/shi × rag2−/− brain. All major white matter tracts heavily express MBP (which is all donor-derived in MBP-null shiverer mice). B, Donor-derived myelin basic protein (MBP green) in sections adjacent or nearly so to matched sections in A. A, Human donor cells identified by an anti-human nuclear antibody (hN red). Representative sagittal images of an engrafted shi/shi × rag2−/− brain, sacrificed at 1 year of age. This review presents an overview of the uses, characteristics, and limitations of the human glial chimeric brain model, while providing a step-by-step protocol for the establishment of these mice.Ĭell transplantation Glial progenitor cell Mouse models Oligodendrocyte progenitor cell Stem cell.Ī-E, Myelination of congenitally hypomyelinated shiverer mice by human fetal tissue-derived glial progenitor cells. Human glial chimeric mice thus provide intriguing preparations by which to investigate the species-specific contributions of human glia to both cognition and human-selective neurodegenerative and neuropsychiatric diseases, as well as the potential for therapeutic glial cell replacement in these disorders. In addition, by neonatally engrafting hGPCs derived from patient- and disease-specific pluripotent stem cells, glial chimeric mice may be produced in which large proportions of all macroglial cells are not only human but also patient and disease specific. When congenitally hypomyelinated mutants are used as hosts, the donor hGPCs generate myelinogenic oligodendrocytes as well as astrocytes, so that the recipient mice develop a largely humanized white matter, with entirely human-derived myelin. Human glial progenitor cells (hGPCs) can engraft, expand, and differentiate into functional oligodendrocytes and astrocytes when transplanted neonatally into murine hosts, in which they outcompete the host glial pool to ultimately colonize and dominate the recipient brains.
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