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

Ulla Milbreta, Junquan Lin, Coline Pinese, William Ong, Jiah Shin Chin, Hitomi Shirahama, Ruifa Mi, Anna Williams, Marie E. Bechler, Jun Wang, Charles ffrench-Constant, Ahmet Hoke, Sing Yian Chew

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Oligodendroglia
Neurotrophin 3
MicroRNAs
Hydrogel
Myelin Sheath
Myelin Basic Protein
Wounds and Injuries
Spinal Cord Injuries
Sprague Dawley Rats
Collagen
Phosphates
Pathology

Keywords

  • CNS
  • electrospinning
  • gene silencing
  • microRNA
  • myelination
  • non-viral
  • oligodendrocytes
  • regeneration
  • scaffold
  • sustained

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Milbreta, U., Lin, J., Pinese, C., Ong, W., Chin, J. S., Shirahama, H., ... Chew, S. Y. (Accepted/In press). Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2018.11.016

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; Hoke, Ahmet; Chew, Sing Yian.

In: Molecular Therapy, 01.01.2019.

Research output: Contribution to journalArticle

Milbreta, U, Lin, J, Pinese, C, Ong, W, Chin, JS, Shirahama, H, Mi, R, Williams, A, Bechler, ME, Wang, J, ffrench-Constant, C, Hoke, A & Chew, SY 2019, 'Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination', Molecular Therapy. https://doi.org/10.1016/j.ymthe.2018.11.016
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 ; Hoke, Ahmet ; Chew, Sing Yian. / Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination. In: Molecular Therapy. 2019.
@article{0ab1040830d942ad9ab3ec2353e03719,
title = "Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination",
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.",
keywords = "CNS, electrospinning, gene silencing, microRNA, myelination, non-viral, oligodendrocytes, regeneration, scaffold, sustained",
author = "Ulla Milbreta and Junquan Lin and Coline Pinese and William Ong and Chin, {Jiah Shin} and Hitomi Shirahama and Ruifa Mi and Anna Williams and Bechler, {Marie E.} and Jun Wang and Charles ffrench-Constant and Ahmet Hoke and Chew, {Sing Yian}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.ymthe.2018.11.016",
language = "English (US)",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination

AU - Milbreta, Ulla

AU - Lin, Junquan

AU - Pinese, Coline

AU - Ong, William

AU - Chin, Jiah Shin

AU - Shirahama, Hitomi

AU - Mi, Ruifa

AU - Williams, Anna

AU - Bechler, Marie E.

AU - Wang, Jun

AU - ffrench-Constant, Charles

AU - Hoke, Ahmet

AU - Chew, Sing Yian

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - CNS

KW - electrospinning

KW - gene silencing

KW - microRNA

KW - myelination

KW - non-viral

KW - oligodendrocytes

KW - regeneration

KW - scaffold

KW - sustained

UR - http://www.scopus.com/inward/record.url?scp=85059313092&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059313092&partnerID=8YFLogxK

U2 - 10.1016/j.ymthe.2018.11.016

DO - 10.1016/j.ymthe.2018.11.016

M3 - Article

C2 - 30611662

AN - SCOPUS:85059313092

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

ER -