title: Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis.
abstract: Neural stem cell (NSC)-based therapies offer potential for neural repair in central nervous system (CNS) inflammatory and degenerative disorders. Typically, these conditions present with multifocal CNS lesions making it impractical to inject NSCs locally, thus mandating optimization of vascular delivery of the cells to involved sites. Here, we analyzed NSCs for expression of molecular effectors of cell migration and found that these cells are natively devoid of E-selectin ligands. Using glycosyltransferase-programmed stereosubstitution (GPS), we glycan engineered the cell surface of NSCs ("GPS-NSCs") with resultant enforced expression of the potent E-selectin ligand HCELL (hematopoietic cell E-/L-selectin ligand) and of an E-selectin-binding glycoform of neural cell adhesion molecule ("NCAM-E"). Following intravenous (i.v.) injection, short-term homing studies demonstrated that, compared with buffer-treated (control) NSCs, GPS-NSCs showed greater neurotropism. Administration of GPS-NSC significantly attenuated the clinical course of experimental autoimmune encephalomyelitis (EAE), with markedly decreased inflammation and improved oligodendroglial and axonal integrity, but without evidence of long-term stem cell engraftment. Notably, this effect of NSC is not a universal property of adult stem cells, as administration of GPS-engineered mouse hematopoietic stem/progenitor cells did not improve EAE clinical course. These findings highlight the utility of cell surface glycan engineering to boost stem cell delivery in neuroinflammatory conditions and indicate that, despite the use of a neural tissue-specific progenitor cell population, neural repair in EAE results from endogenous repair and not from direct, NSC-derived cell replacement.
authors.affiliation: Department of Dermatology Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia.
authors.forename: Jasmeen S
authors.initials: JS
authors.lastname: Merzaban
authors.affiliation: Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.affiliation: Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Starossom
authors.affiliation: Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Dermatology.
authors.forename: Jack
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia.
authors.forename: Amal J
authors.initials: AJ
authors.lastname: Ali
authors.affiliation: Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Olah
authors.affiliation: Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia.
authors.forename: Ayman F
authors.initials: AF
authors.lastname: Abuelela
authors.affiliation: Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.affiliation: Department of Dermatology Department of Medicine, Harvard Skin Disease Research Center rsackstein@partners.org.
authors.forename: Robert
authors.initials: R
authors.lastname: Sackstein
mesh_terms: D000818:Animals; D002465:Cell Movement; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D015316:Genetic Therapy; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism* / Q000637:transplantation; D011134:Polysaccharides / Q000378:metabolism*; D019087:Selectins / Q000378:metabolism
chemical_list: D018960:Hyaluronan Receptors; D019006:Neural Cell Adhesion Molecules; D011134:Polysaccharides; D019087:Selectins; C497483:CD44 protein, human
keywords: HCELL; exofucosylation; glycan engineering; multiple sclerosis; neural stem cell