Abstract
An obstacle to early stem cell transplantation into the acutely injured spinal cord is poor survival of transplanted cells. Transplantation of embryonic stem cells as substrate adherent embryonic stem cell-derived neural aggregates (SENAs) consisting mainly of neurons and radial glial cells has been shown to enhance survival of grafted cells in the injured mouse brain. In the attempt to promote the beneficial function of these SENAs, murine embryonic stem cells constitutively overexpressing the neural cell adhesion molecule L1 which favors axonal growth and survival of grafted and imperiled cells in the inhibitory environment of the adult mammalian central nervous system were differentiated into SENAs and transplanted into the spinal cord three days after compression lesion. Mice transplanted with L1 overexpressing SENAs showed improved locomotor function when compared to mice injected with wild-type SENAs. L1 overexpressing SENAs showed an increased number of surviving cells, enhanced neuronal differentiation and reduced glial differentiation after transplantation when compared to SENAs not engineered to overexpress L1. Furthermore, L1 overexpressing SENAs rescued imperiled host motoneurons and parvalbumin-positive interneurons and increased numbers of catecholaminergic nerve fibers distal to the lesion. In addition to encouraging the use of embryonic stem cells for early therapy after spinal cord injury L1 overexpression in the microenvironment of the lesioned spinal cord is a novel finding in its functions that would make it more attractive for pre-clinical studies in spinal cord regeneration and most likely other diseases of the nervous system.
Highlights
Spinal cord injury results in a change, either temporary or permanent, in its motor, sensory, or autonomic functions
A murine Embryonic stem (ES) cell line constitutively expressing L1 at all stages of differentiation [13] was differentiated by the stem cell-derived neural aggregates (SENAs) protocol prior to transplantation in this study to combine the beneficial effects of L1 overexpression and the SENA differentiation protocol to overcome the inhibitory environment of the central nervous system and promote functional recovery after spinal cord injury
The extension-flexion ratio, a parameter to judge voluntary movements without body weight support, revealed no significant differences among the experimental groups of mice, L1 overexpressing SENAs showed a tendency towards improved motor function when compared to wild-type SENAs and sham-injected PBS three and six weeks after injury (Fig. 1D, H)
Summary
Spinal cord injury results in a change, either temporary or permanent, in its motor, sensory, or autonomic functions. L1 overexpressing SENAs have previously been shown to enhance the survival of grafted cells and to rescue endogenous dopaminergic neurons in a mouse model of Parkinson’s disease [16]. Based on these findings, a murine ES cell line constitutively expressing L1 at all stages of differentiation [13] was differentiated by the SENA protocol prior to transplantation in this study to combine the beneficial effects of L1 overexpression and the SENA differentiation protocol to overcome the inhibitory environment of the central nervous system and promote functional recovery after spinal cord injury. L1 overexpressing SENAs rescue endogenous spinal cord interneurons and motoneurons and promote the regrowth of catecholaminergic nerve fibers distal to the lesion site
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