Human Oligodendrogenic Neural Progenitor Cells Delivered with Chondroitinase ABC Facilitate Functional Repair of Chronic Spinal Cord Injury

Satoshi Nori; Mohamad Khazaei; Christopher S Ahuja; Kazuya Yokota; Jan-Eric Ahlfors; Yang Liu; Jian Wang; Shinsuke Shibata; Jonathon Chio; Marian H Hettiaratchi; Tobias Führmann; Molly S Shoichet; Michael G Fehlings

doi:10.1016/j.stemcr.2018.10.017

Human Oligodendrogenic Neural Progenitor Cells Delivered with Chondroitinase ABC Facilitate Functional Repair of Chronic Spinal Cord Injury

Stem Cell Reports. 2018 Dec 11;11(6):1433-1448. doi: 10.1016/j.stemcr.2018.10.017. Epub 2018 Nov 21.

Authors

Affiliations

¹ Division of Genetics and Development, Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada; Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinju-ku, Tokyo 160-8582, Japan.
² Division of Genetics and Development, Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.
³ Division of Genetics and Development, Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
⁴ New World Laboratories Inc., 500 Boulevard Cartier Quest, Laval, QC H7V 5B7, Canada.
⁵ Electron Microscope Laboratory, Keio University School of Medicine, 35 Shinanomachi, Shinju-ku, Tokyo 160-8582, Japan.
⁶ Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON M5S 3E5, Canada.
⁷ Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON M5S 3E5, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada; Institute of Biomaterials & Biomedical Engineering, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
⁸ Division of Genetics and Development, Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Surgery and Spinal Program, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Surgery, Division of Anatomy, Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada. Electronic address: michael.fehlings@uhn.ca.

Abstract

Treatment of chronic spinal cord injury (SCI) is challenging due to cell loss, cyst formation, and the glial scar. Previously, we reported on the therapeutic potential of a neural progenitor cell (NPC) and chondroitinase ABC (ChABC) combinatorial therapy for chronic SCI. However, the source of NPCs and delivery system required for ChABC remained barriers to clinical application. Here, we investigated directly reprogrammed human NPCs biased toward an oligodendrogenic fate (oNPCs) in combination with sustained delivery of ChABC using an innovative affinity release strategy in a crosslinked methylcellulose biomaterial for the treatment of chronic SCI in an immunodeficient rat model. This combinatorial therapy increased long-term survival of oNPCs around the lesion epicenter, facilitated greater oligodendrocyte differentiation, remyelination of the spared axons by engrafted oNPCs, enhanced synaptic connectivity with anterior horn cells and neurobehavioral recovery. This combinatorial therapy is a promising strategy to regenerate the chronically injured spinal cord.

Keywords: ChABC; cell transplantation; chronic spinal cord injury; combinatorial therapy; crosslinked methylcellulose hydrogel; glial scar; neural progenitor cells; oligodendrocyte; regenerative medicine; remyelination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anterior Horn Cells / cytology
Anterior Horn Cells / metabolism
Axons / metabolism
Axons / ultrastructure
Cell Differentiation
Cell Lineage
Cell Survival
Chondroitin ABC Lyase / metabolism*
Chondroitin Sulfate Proteoglycans / metabolism
Chronic Disease
Cicatrix / pathology
Cross-Linking Reagents / chemistry
Female
Humans
Methylcellulose / chemistry
Motor Activity
Neural Stem Cells / transplantation*
Neuralgia / pathology
Neuralgia / physiopathology
Neuronal Plasticity
Oligodendroglia / transplantation*
Rats
Recovery of Function*
Remyelination
Spinal Cord Injuries / physiopathology*
Synapses / metabolism
Synapses / ultrastructure

Substances

Chondroitin Sulfate Proteoglycans
Cross-Linking Reagents
Methylcellulose
Chondroitin ABC Lyase

Grants and funding

CIHR/Canada