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Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury. PLoS One 2017;12(8):e0182339

Date

08/05/2017

Pubmed ID

28771534

Pubmed Central ID

PMC5542671

DOI

10.1371/journal.pone.0182339

Scopus ID

2-s2.0-85026755609   62 Citations

Abstract

Traumatic spinal cord injuries (SCIs) affect millions of people worldwide; the majority of whom are in the chronic phase of their injury. Unfortunately, most current treatments target the acute/subacute injury phase as the microenvironment of chronically injured cord consists of a well-established glial scar with inhibitory chondroitin sulfate proteoglycans (CSPGs) which acts as a potent barrier to regeneration. It has been shown that CSPGs can be degraded in vivo by intrathecal Chondroitinase ABC (ChABC) to produce a more permissive environment for regeneration by endogenous cells or transplanted neural stem cells (NSCs) in the subacute phase of injury. Using a translationally-relevant clip-contusion model of cervical spinal cord injury in mice we sought to determine if ChABC pretreatment could modify the harsh chronic microenvironment to enhance subsequent regeneration by induced pluripotent stem cell-derived NSCs (iPS-NSC). Seven weeks after injury-during the chronic phase-we delivered ChABC by intrathecal osmotic pump for one week followed by intraparenchymal iPS-NSC transplant rostral and caudal to the injury epicenter. ChABC administration reduced chronic-injury scar and resulted in significantly improved iPSC-NSC survival with clear differentiation into all three neuroglial lineages. Neurons derived from transplanted cells also formed functional synapses with host circuits on patch clamp analysis. Furthermore, the combined treatment led to recovery in key functional muscle groups including forelimb grip strength and measures of forelimb/hindlimb locomotion assessed by Catwalk. This represents important proof-of-concept data that the chronically injured spinal cord can be 'unlocked' by ChABC pretreatment to produce a microenvironment conducive to regenerative iPS-NSC therapy.

Author List

Suzuki H, Ahuja CS, Salewski RP, Li L, Satkunendrarajah K, Nagoshi N, Shibata S, Fehlings MG

Author

Kajana Satkunendrarajah PhD Assistant Professor in the Neurosurgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Differentiation
Cells, Cultured
Cervical Cord
Chondroitin ABC Lyase
Chronic Disease
Cicatrix
Evoked Potentials
Forelimb
Induced Pluripotent Stem Cells
Locomotion
Mice
Mice, Inbred C57BL
Nerve Regeneration
Neural Stem Cells
Neurons
Recovery of Function
Spinal Cord
Spinal Cord Injuries
Synapses