Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination

Milbreta, Ulla, Lin, Junquan, Pinese, Coline, Ong, William, Chin, Jiah Shin, Shirahama, Hitomi, Mi, Ruifa, Williams, Anna, Bechler, Marie E., Wang, Jun, ffrench-Constant, Charles ORCID: https://orcid.org/0000-0002-5621-3377, Hoke, Ahmet and Chew, Sing Yian (2018) Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination. Molecular Therapy, 27 (2). pp. 411-423. ISSN 1525-0016

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Abstract

The loss of oligodendrocytes (OLs) and subsequently myelin sheaths following injuries or pathologies in the CNS leads to debilitating functional deficits. Unfortunately, effective methods of remyelination remain limited. Here, we present a scaffolding system that enables sustained non-viral delivery of microRNAs (miRs) to direct OL differentiation, maturation, and myelination. We show that miR-219/miR-338 promoted primary rat OL differentiation and myelination in vitro. Using spinal cord injury as a proof-of-concept, we further demonstrate that miR-219/miR-338 could also be delivered non-virally in vivo using an aligned fiber-hydrogel scaffold to enhance remyelination after a hemi-incision injury at C5 level of Sprague-Dawley rats. Specifically, miR-219/miR-338 mimics were incorporated as complexes with the carrier, TransIT-TKO (TKO), together with neurotrophin-3 (NT-3) within hybrid scaffolds that comprised poly(caprolactone-co-ethyl ethylene phosphate) (PCLEEP)-aligned fibers and collagen hydrogel. After 1, 2, and 4 weeks post-treatment, animals that received NT-3 and miR-219/miR-338 treatment preserved a higher number of Olig2+ oligodendroglial lineage cells as compared with those treated with NT-3 and negative scrambled miRs (Neg miRs; p < 0.001). Additionally, miR-219/miR-338 increased the rate and extent of differentiation of OLs. At the host-implant interface, more compact myelin sheaths were observed when animals received miR-219/miR-338. Similarly within the scaffolds, miR-219/miR-338 samples contained significantly more myelin basic protein (MBP) signals (p < 0.01) and higher myelination index (p < 0.05) than Neg miR samples. These findings highlight the potential of this platform to promote remyelination within the CNS.

Item Type: Article
Additional Information: Funding Information: Partial funding support was provided by the Singapore National Research Foundation under its NMRC-CBRG grants ( NMRC/CBRG/0002/2012 and NMRC/CBRG/0096/2015 ) and administered by the Singapore Ministry of Health’s National Medical Research Council . The MOE Tier 1 grant ( RG148/14 ) and the RRIS Rehabilitation Research Grant ( RRG1/16004 ) are acknowledged. Partial funding support from the Dr. Miriam and Sheldon G. Adelson Research Foundation is also acknowledged. The authors would like to thank Prof. William Stallcup for his generous gift of the anti-PDGFRα antibody, and Prof. Jonah Chan for the meaningful discussions on oligodendrocyte differentiation and markers expressions. Funding Information: Partial funding support was provided by the Singapore National Research Foundation under its NMRC-CBRG grants (NMRC/CBRG/0002/2012 and NMRC/CBRG/0096/2015) and administered by the Singapore Ministry of Health's National Medical Research Council. The MOE Tier 1 grant (RG148/14) and the RRIS Rehabilitation Research Grant (RRG1/16004) are acknowledged. Partial funding support from the Dr. Miriam and Sheldon G. Adelson Research Foundation is also acknowledged. The authors would like to thank Prof. William Stallcup for his generous gift of the anti-PDGFR? antibody, and Prof. Jonah Chan for the meaningful discussions on oligodendrocyte differentiation and markers expressions.
Uncontrolled Keywords: cns,electrospinning,gene silencing,microrna,myelination,non-viral,oligodendrocytes,regeneration,scaffold,sustained,molecular medicine,molecular biology,genetics,pharmacology,drug discovery ,/dk/atira/pure/subjectarea/asjc/1300/1313
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 15 Jul 2022 14:30
Last Modified: 12 Aug 2022 05:37
URI: https://ueaeprints.uea.ac.uk/id/eprint/86229
DOI: 10.1016/j.ymthe.2018.11.016

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