Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome.
Several studies have reported functional improvement after transplantation of neural stem cells into injured spinal cord. We now provide evidence that grafting of adult neural stem cells into a rat thoracic spinal cord weight-drop injury improves motor recovery but also causes aberrant axonal sprouting associated with allodynia-like hypersensitivity of forepaws. Transduction of neural stem cells with neurogenin-2 before transplantation suppressed astrocytic differentiation of engrafted cells and prevented graft-induced sprouting and allodynia. Transduction with neurogenin-2 also improved the positive effects of engrafted stem cells, including increased amounts of myelin in the injured area, recovery of hindlimb locomotor function and hindlimb sensory responses, as determined by functional magnetic resonance imaging. These findings show that stem cell transplantation into injured spinal cord can cause severe side effects and call for caution in the consideration of clinical trials.
Hofstetter
Christoph P
CP
Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. christoph.hofstetter@neuro.ki.se
Holmström
Niklas A V
NA
Lilja
Johan A
JA
Schweinhardt
Petra
P
Hao
Jinxia
J
Spenger
Christian
C
Wiesenfeld-Hallin
Zsuzsanna
Z
Kurpad
Shekar N
SN
Frisén
Jonas
J
Olson
Lars
L
D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001522:Behavior, Animal; D001921:Brain / Q000098:blood supply / Q000503:physiopathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002452:Cell Count; D004195:Disease Models, Animal; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D007150:Immunohistochemistry / Q000379:methods; D007797:Laminin / Q000145:classification / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D009043:Motor Activity / Q000502:physiology; D009186:Myelin Sheath / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009434:Neural Pathways / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D010146:Pain / Q000209:etiology / Q000503:physiopathology; D010147:Pain Measurement; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000628:therapy*; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D013234:Stem Cells / Q000502:physiology*; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods; D014404:Tubulin / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D015740:Calcitonin Gene-Related Peptide; D049452:Green Fluorescent Proteins; D007797:Laminin; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D009842:Oligopeptides; D010100:Oxygen; D010751:Phosphopyruvate Hydratase; D017461:Receptors, Atrial Natriuretic Factor; D014404:Tubulin; C102938:Neurog2 protein, mouse; C111711:RNAIII inhibiting peptide; C073616:atrial natriuretic factor receptor C