Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF).
Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination. Impact statement Nanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS.
Centre for Regenerative Medicine, University of Edinburgh, 5, Little France Drive, Edinburgh, EH16 4UU, UK.
Sonja
S
Rittchen
Centre for Regenerative Medicine, University of Edinburgh, 5, Little France Drive, Edinburgh, EH16 4UU, UK.
Amanda
A
Boyd
Centre for Regenerative Medicine, University of Edinburgh, 5, Little France Drive, Edinburgh, EH16 4UU, UK.
Alasdair
A
Burns
Department of Biomedical Engineering, Department of Immunobiology, Yale School of Engineering and Applied Science and Yale School of Medicine, 55 Prospect Street, New Haven, CT, 06511, USA.
Jason
J
Park
Department of Biomedical Engineering, Department of Immunobiology, Yale School of Engineering and Applied Science and Yale School of Medicine, 55 Prospect Street, New Haven, CT, 06511, USA.
Tarek M
TM
Fahmy
John van Geest Centre for Brain Repair, University of Cambridge, Addenbrooke's Hospital, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK. Electronic address: smm1001@cam.ac.uk.
Su
S
Metcalfe
Centre for Regenerative Medicine, University of Edinburgh, 5, Little France Drive, Edinburgh, EH16 4UU, UK. Electronic address: Anna.Williams@ed.ac.uk.
Anna
A
Williams
D000818:Animals; D000941:Antigens / Q000737:chemistry*; D001369:Axons / Q000502:physiology; D001672:Biocompatible Materials / Q000737:chemistry; D002454:Cell Differentiation; D002809:Chondroitin Sulfates / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D016503:Drug Delivery Systems; D006046:Gold / Q000737:chemistry; D053605:Leukemia Inhibitory Factor / Q000737:chemistry*; D008244:Lysophosphatidylcholines / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009103:Multiple Sclerosis / Q000628:therapy; D009186:Myelin Sheath / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D058953:Neural Stem Cells / Q000166:cytology*; D009836:Oligodendroglia / Q000166:cytology*; D011509:Proteoglycans / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D001672:Biocompatible Materials; D002809:Chondroitin Sulfates; D016207:Cytokines; D006046:Gold; D053605:Leukemia Inhibitory Factor; D008244:Lysophosphatidylcholines; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4; C507838:Lif protein, mouse
Leukaemia inhibitory factor; Multiple sclerosis; Myelin; Nanotherapy; Remyelination