Abstract
The L1 cell adhesion molecule promotes neurite outgrowth and neuronal survival in homophilic and heterophilic interactions and enhances neurite outgrowth and neuronal survival homophilically, i.e. by self binding. We investigated whether exploitation of homophilic and possibly also heterophilic mechanisms of neural stem cells overexpressing the full-length transmembrane L1 and a secreted trimer engineered to express its extracellular domain would be more beneficial for functional recovery of the compression injured spinal cord of adult mice than stem cells overexpressing only full-length L1 or the parental, non-engineered cells. Here we report that stem cells expressing trimeric and full-length L1 are indeed more efficient in promoting locomotor recovery when compared to stem cells overexpressing only full-length L1 or the parental stem cells. The trimer expressing stem cells were also more efficient in reducing glial scar volume and expression of chondroitin sulfates and the chondroitin sulfate proteoglycan NG2. They were also more efficient in enhancing regrowth/sprouting and/or preservation of serotonergic axons, and remyelination and/or myelin sparing. Moreover, degeneration/dying back of corticospinal cord axons was prevented more by the trimer expressing stem cells. These results encourage the view that stem cells engineered to drive the beneficial functions of L1 via homophilic and heterophilic interactions are functionally optimized and may thus be of therapeutic value.
Highlights
The adhesion molecule L1 has been shown to favour conducive processes in a generally inhibitory environment [1,2,3]
Between 3 and 6 weeks after injury, mice transplanted with trimeric L1 (tL1) neural stem cells (NSCs) showed increased mean Basso Mouse Score (BMS) score values when compared to the other groups transplanted with L1 NSCs at 5 and 6 weeks (p,0.01) or wt NSCs at 3, 4, 5 and 6 weeks (p,0.01) at the different time points indicating superior locomotor recovery with the maximal mean score values being 5.160.16 at 5 weeks (Fig. 2a)
Mice transplanted with tL1 NSCs show better recovery when compared to mice transplanted with L1 NSCs at the time points indicated (* p,0.05, ** p,0.01) or when compared to mice transplanted with wt NSCs (# p,0.05, ## p,0.01). (Overall recovery index = [(X7+n2X7)/(X02X7)]6100, where X0, X7 and X7+n are values prior to injury, seven days after injury, and a time-point n days after injury, respectively). doi:10.1371/journal.pone.0046223.g002
Summary
The adhesion molecule L1 has been shown to favour conducive processes in a generally inhibitory environment [1,2,3]. L1 is a member of the immunoglobulin superfamily and promotes neurite outgrowth in a homophilic E. self-binding) manner [4]. In vitro and in vivo studies support the view that homophilic interactions of L1 promote neurite outgrowth and neuronal migration, and neuronal survival [4,5,6,7,8,9,10]. L1 is involved in modification of synaptic efficacy both in vitro and in vivo as well as in learning and memory [11,12]. L1 acts via heterophilic binding mechanisms [17,18,19,20,21,22]
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