Combination of engineered Schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury.
Transplantation of Schwann cells (SCs) is a promising therapeutic strategy for spinal cord repair. SCs introduced into lesions support axon regeneration, but because these axons do not exit the transplant, additional approaches with SCs are needed. Here, we transplanted SCs genetically modified to secrete a bifunctional neurotrophin (D15A) and chondroitinase ABC (ChABC) into a subacute contusion injury in rats. We examined the effects of these modifications on graft volume, SC number, degradation of chondroitin sulfate proteoglycans (CSPGs), astrogliosis, SC myelination of axons, propriospinal and supraspinal axon numbers, locomotor outcome (BBB scoring, CatWalk gait analysis), and mechanical and thermal sensitivity on the hind paws. D15A secreted from transplanted SCs increased graft volume and SC number and myelinated axon number. SCs secreting ChABC significantly decreased CSPGs, led to some egress of SCs from the graft, and increased propriospinal and 5-HT-positive axons in the graft. SCs secreting both D15A and ChABC yielded the best responses: (1) the largest number of SC myelinated axons, (2) more propriospinal axons in the graft and host tissue around and caudal to it, (3) more corticospinal axons closer to the graft and around and caudal to it, (4) more brainstem neurons projecting caudal to the transplant, (5) increased 5-HT-positive axons in the graft and caudal to it, (6) significant improvement in aspects of locomotion, and (7) improvement in mechanical and thermal allodynia. This is the first evidence that the combination of SC transplants engineered to secrete neurotrophin and chondroitinase further improves axonal regeneration and locomotor and sensory function.
Miami Project to Cure Paralysis, Department of Neurological Surgery, Neuroscience Program, Interdisciplinary Stem Cell Institute, and Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, United Kingdom, and Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan, 9808574.
Haruo
H
Kanno
Yelena
Y
Pressman
Alison
A
Moody
Randall
R
Berg
Elizabeth M
EM
Muir
John H
JH
Rogers
Hiroshi
H
Ozawa
Eiji
E
Itoi
Damien D
DD
Pearse
Mary Bartlett
MB
Bunge
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D057005:Bioengineering; D019765:Chondroitin ABC Lyase / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006930:Hyperalgesia / Q000503:physiopathology; D008124:Locomotion / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000378:metabolism*; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D012583:Schwann Cells / Q000378:metabolism* / Q000637:transplantation; D012701:Serotonin; D013119:Spinal Cord Injuries / Q000503:physiopathology* / Q000601:surgery*
D008164:Luminescent Proteins; D009414:Nerve Growth Factors; D012701:Serotonin; D019765:Chondroitin ABC Lyase
Schwann cell; cell transplantation; chondroitinase; glial scar; spinal cord injury