Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury.
Transplantation of neural stem cells (NSCs) in the injured spinal cord has been shown to improve functional outcome; however, recent evidence has demonstrated forelimb allodynia following transplantation of embryonic NSCs. The aim of this study was to investigate whether transplantation of murine C17.2 NSCs alone or transfected with glial-derived neurotrophic factor (C17.2/GDNF) would induce allodynia in transplanted spinal cord-injured animals. One week after a T8-level spinal cord injury (SCI), C17.2, C17.2/GDNF or normal saline was injected at the injury site. Locomotor function and sensory recovery to thermal and mechanical stimuli were then measured. Spinal cords were processed immunohistochemically at the injury/transplantation site for characterization of NSC survival and differentiation; and at the cervicothoracic level for calcitonin gene-related peptide (CGRP), a neuropeptide expressed in dorsal horn nocioceptive neurons, and growth-associated protein-43 (GAP43), a marker of neuronal sprouting. Locomotor function was not significantly improved following NSC transplantation at any time (P >0.05). Significant forelimb thermal and mechanical allodynia were observed following transplantation with both NSC populations (P <0.05). The C17.2 and C17.2/GDNF NSCs survived and differentiated into a predominately astrocytic population. Calcitonin gene-related peptide and GAP43 immunoreactivity significantly increased and co-localized in cervicothoracic dorsal horn laminae I-III following C17.2 and C17.2/GDNF transplantation. This study demonstrated that murine C17.2 NSCs differentiated primarily into astrocytes when transplanted into the injured spinal cord, and resulted in thermal and mechanical forelimb allodynia. Sprouting of nocioceptive afferents occurred rostral to the injury/transplantation site only in allodynic animals, suggesting a principal role in this aberrant pain state. Further, a difference in the degree of allodynia was noted between C17.2- and C17.2/GDNF transplant-treated groups; this difference correlated with the level of CGRP/GAP43 immunoreactivity and sprouting observed in the cervicothoracic dorsal horns. Both allodynia- and CGRP/GAP43-positive afferent sprouting were less in the C17.2/GDNF group compared to the C17.2 group, suggesting a possible protective or analgesic effect of GDNF on post-injury neuropathic pain.
Macias
Melissa Y
MY
Department of Neurosurgery, Neuroscience Research Laboratories, Medical College of Wisconsin and Clement J Zablocki VA Medical Center, Milwaukee, WI 53226, USA.
Syring
Mara B
MB
Pizzi
Michael A
MA
Crowe
Maria J
MJ
Alexanian
Arshak R
AR
Kurpad
Shekar N
SN
D000818:Animals; D001369:Axons / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D005260:Female; D005552:Forelimb / Q000503:physiopathology; D019922:GAP-43 Protein / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology; D006614:Hindlimb / Q000503:physiopathology; D006358:Hot Temperature / Q000009:adverse effects; D007150:Immunohistochemistry; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000503:physiopathology*; D020671:Posterior Horn Cells / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000601:surgery*; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D013314:Stress, Mechanical; D014183:Transplantation, Heterologous
D019922:GAP-43 Protein; D051100:Glial Cell Line-Derived Neurotrophic Factor; D015740:Calcitonin Gene-Related Peptide