Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome

Abstract

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.

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

“…Are astrocytes sufficient and required for chronic pain sensitization?-Spinal astrocytes appear to be sufficient to produce persistent pain. Implantation of neural stem cells into the injured spinal cord improves motor recovery and causes allodynia-like hypersensitivity of the forepaws (Hofstetter et al, 2005;Macias et al, 2006). Because most of the stem cells that are implanted in the spinal cord become astrocytes, implantation-induced allodynia is likely to be attributed to the action of astrocytes.…”

“…This allodynia is associated with aberrant sprouting of pain-mediating calcitonin gene-related peptide (CGRP)-positive fibers in the dorsal horn due to the release of growth factors (e.g. nerve growth factor) from astrocytes (Hofstetter et al, 2005). In contrast, sprouting and allodynia are prevented if neural stem cells are transfected with neurogenin-2 before transplantation to suppress the generation of astrocytes (Hofstetter et al, 2005).…”

“…nerve growth factor) from astrocytes (Hofstetter et al, 2005). In contrast, sprouting and allodynia are prevented if neural stem cells are transfected with neurogenin-2 before transplantation to suppress the generation of astrocytes (Hofstetter et al, 2005).…”

Clinical canine spinal cord injury provides an opportunity to examine the issues in translating laboratory techniques into practical therapy

“…Even patients who have very severe SCI will still be able to demonstrate allodynia, which is the most feared complication of cellular transplantation into the spinal cord. 90 However, this group of patients is limited in its ability to express other potential deleterious effects of intraspinal transplantation, for instance on locomotion, as their predicted recovery is so limited anyway.…”

International spinal research trust research strategy. III: A discussion document

“…However, forcing stem cells into a distinct lineage before transplantation avoids allodynia and improves functional outcome. 52 The benefits of grafting differentiated, purified cells require further study. These data indicate that care should be taken that preclinical studies should specifically examine the adverse effects of cell therapies.…”