Abstract
BackgroundTraumatic spinal cord injury (SCI) results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns) were prospectively isolated based on fluorescence-activated cell sorting for a CD133+ and CD24−/lo population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.Methods and FindingshCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein.ConclusionsThe results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the “window of opportunity” for intervention.
Highlights
Traumatic spinal cord injury (SCI) results in partial or complete paralysis along with sensory loss below the level ofinjury
We have previously reported on the sub-acute transplantation of human neural stem cells, which are lineage restricted to generate neurons, oligodendrocytes, and astrocytes, into a NOD-scid SCI model. hCNS-SCns are prospectively isolated based on fluorescence-activated cell sorting (FACS) for a CD133+ and CD242/lo population from fetal brain and grown as neurospheres [18]
Results hCNS-SCns promote locomotor recovery To investigate whether hCNS-SCns can contribute to long-term locomotor recovery in an early chronic SCI model mice received grafts of hCNS-SCns, human fibroblast (hFbs), or a vehicle control injection 30 days post contusion injury
Summary
Traumatic spinal cord injury (SCI) results in partial or complete paralysis along with sensory loss below the level ofinjury. The pathology of SCI is characterized by the loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. SCI therapies can target acute, sub-acute, or chronic time points post-injury. Traumatic spinal cord injury (SCI) results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. HCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery
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