Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis
Starossom, Sarah C.
Ali, Amal J.
Khoury, Samia J.
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AbstractNeural 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.
CitationMerzaban JS, Imitola J, Starossom SC, Zhu B, Wang Y, et al. (2015) Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis. Glycobiology 25: 1392–1409. Available: http://dx.doi.org/10.1093/glycob/cwv046.
SponsorsThis effort was supported by National Institutes of Health grants PO1 HL107146 [NHLBI Program of Excellence in Glycosciences (R.S.)], RO1 HL73714 (R.S.), RO1 HL60528 (R.S.), AI043496 (S.J.K.) and AI071448 (S.J.K.). This work was also supported by the Edward and Dana Slatkin Research Fund and the Brourman Family Fund (R.S.), and by a National Multiple Sclerosis Society grant RG3945 (S.J.K). The King Abdullah University of Science and Technology Faculty Baseline Research Funding Program (J.S.M.) also supported this work. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
PublisherOxford University Press (OUP)
PubMed Central IDPMC4634313
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