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Ectopic expression of polysialylated neural cell adhesion molecule in adult macaque Schwann cells promotes their migration and remyelination potential in the central nervous system.

Bachelin C, Zujovic V, Buchet D, Mallet J, Baron-Van Evercooren A - Brain (2009)

Bottom Line: In vitro, we found that ectopic expression of polysialylate promoted adult macaque Schwann cell migration and improved their integration among astrocytes in vitro without modifying their antigenic properties as either non-myelinating or pro-myelinating.These greater performances of sialyltransferase expressing Schwann cell correlated with their sustained expression of polysialylated neural cell adhesion molecule at early times when migrating from the graft to the lesion, and its progressive downregulation at later times during remyelination.These results underline the potential therapeutic benefit to genetically modify Schwann cells to overcome their poor migration capacity and promote their repair potential in demyelinating disorders of the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere, Universite Pierre et Marie Curie-Paris 6, UMR-S975, Paris, France.

ABSTRACT
Recent findings suggested that inducing neural cell adhesion molecule polysialylation in rodents is a promising strategy for promoting tissue repair in the injured central nervous system. Since autologous grafting of Schwann cells is one potential strategy to promote central nervous system remyelination, it is essential to show that such a strategy can be translated to adult primate Schwann cells and is of interest for myelin diseases. Adult macaque Schwann cells were transduced with a lentiviral vector encoding sialyltransferase, an enzyme responsible for neural cell adhesion molecule polysialylation. In vitro, we found that ectopic expression of polysialylate promoted adult macaque Schwann cell migration and improved their integration among astrocytes in vitro without modifying their antigenic properties as either non-myelinating or pro-myelinating. In addition, forced expression of polysialylate in adult macaque Schwann cells decreased their adhesion with sister cells. To investigate the ability of adult macaque Schwann cells to integrate and migrate in vivo, focally induced demyelination was targeted to the spinal cord dorsal funiculus of nude mice, and both control and sialyltransferase expressing Schwann cells overexpressing green fluorescein protein were grafted remotely from the lesion site. Analysis of the spatio-temporal distribution of the grafted Schwann cells performed in toto and in situ, showed that in both groups, Schwann cells migrated towards the lesion site. However, migration of sialyltransferase expressing Schwann cells was more efficient than that of control Schwann cells, leading to their accelerated recruitment by the lesion. Moreover, ectopic expression of polysialylated neural cell adhesion molecule promoted adult macaque Schwann cell interaction with reactive astrocytes when exiting the graft, and their 'chain-like' migration along the dorsal midline. The accelerated migration of sialyltransferase expressing Schwann cells to the lesion site enhanced their ability to compete for myelin repair with endogenous cells, while control Schwann cells were unable to do so. Finally, remyelination by the exogenous sialyltransferase expressing Schwann cells restored the normal distribution of paranodal and nodal elements on the host axons. These greater performances of sialyltransferase expressing Schwann cell correlated with their sustained expression of polysialylated neural cell adhesion molecule at early times when migrating from the graft to the lesion, and its progressive downregulation at later times during remyelination. These results underline the potential therapeutic benefit to genetically modify Schwann cells to overcome their poor migration capacity and promote their repair potential in demyelinating disorders of the central nervous system.

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PSA NCAM expression by the grafted STX-SC. Double immuno-labelling of horizontal frozen sections for PSA-NCAM (red) and STX-SC (green). (A–C) At 7 d.p.t., the majority of STX-SC (arrows) express PSA-NCAM on their membrane. (D–F) Fourteen d.p.t., the number of STX-SC expressing PSA-NCAM (arrows) and PSA intensity is decreased. Inserts show higher magnifications of the dashed box areas illustrating double labelled cells.
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Figure 8: PSA NCAM expression by the grafted STX-SC. Double immuno-labelling of horizontal frozen sections for PSA-NCAM (red) and STX-SC (green). (A–C) At 7 d.p.t., the majority of STX-SC (arrows) express PSA-NCAM on their membrane. (D–F) Fourteen d.p.t., the number of STX-SC expressing PSA-NCAM (arrows) and PSA intensity is decreased. Inserts show higher magnifications of the dashed box areas illustrating double labelled cells.

Mentions: Finally, we investigated whether the greater propensity of STX-GFP-Schwann cells to integrate and migrate in the CNS was correlated with PSA expression by the grafted Schwann cells. Immunohistochemistry for PSA showed that only STX-SC expressed PSA. This expression was transient, since PSA was clearly detected at 7 d.p.t. (Fig. 8A and C), but was weaker at 14 d.p.t. (Fig. 8D and F) and no longer detectable by 28 d.p.t. (data not shown).Figure 8


Ectopic expression of polysialylated neural cell adhesion molecule in adult macaque Schwann cells promotes their migration and remyelination potential in the central nervous system.

Bachelin C, Zujovic V, Buchet D, Mallet J, Baron-Van Evercooren A - Brain (2009)

PSA NCAM expression by the grafted STX-SC. Double immuno-labelling of horizontal frozen sections for PSA-NCAM (red) and STX-SC (green). (A–C) At 7 d.p.t., the majority of STX-SC (arrows) express PSA-NCAM on their membrane. (D–F) Fourteen d.p.t., the number of STX-SC expressing PSA-NCAM (arrows) and PSA intensity is decreased. Inserts show higher magnifications of the dashed box areas illustrating double labelled cells.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
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Figure 8: PSA NCAM expression by the grafted STX-SC. Double immuno-labelling of horizontal frozen sections for PSA-NCAM (red) and STX-SC (green). (A–C) At 7 d.p.t., the majority of STX-SC (arrows) express PSA-NCAM on their membrane. (D–F) Fourteen d.p.t., the number of STX-SC expressing PSA-NCAM (arrows) and PSA intensity is decreased. Inserts show higher magnifications of the dashed box areas illustrating double labelled cells.
Mentions: Finally, we investigated whether the greater propensity of STX-GFP-Schwann cells to integrate and migrate in the CNS was correlated with PSA expression by the grafted Schwann cells. Immunohistochemistry for PSA showed that only STX-SC expressed PSA. This expression was transient, since PSA was clearly detected at 7 d.p.t. (Fig. 8A and C), but was weaker at 14 d.p.t. (Fig. 8D and F) and no longer detectable by 28 d.p.t. (data not shown).Figure 8

Bottom Line: In vitro, we found that ectopic expression of polysialylate promoted adult macaque Schwann cell migration and improved their integration among astrocytes in vitro without modifying their antigenic properties as either non-myelinating or pro-myelinating.These greater performances of sialyltransferase expressing Schwann cell correlated with their sustained expression of polysialylated neural cell adhesion molecule at early times when migrating from the graft to the lesion, and its progressive downregulation at later times during remyelination.These results underline the potential therapeutic benefit to genetically modify Schwann cells to overcome their poor migration capacity and promote their repair potential in demyelinating disorders of the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere, Universite Pierre et Marie Curie-Paris 6, UMR-S975, Paris, France.

ABSTRACT
Recent findings suggested that inducing neural cell adhesion molecule polysialylation in rodents is a promising strategy for promoting tissue repair in the injured central nervous system. Since autologous grafting of Schwann cells is one potential strategy to promote central nervous system remyelination, it is essential to show that such a strategy can be translated to adult primate Schwann cells and is of interest for myelin diseases. Adult macaque Schwann cells were transduced with a lentiviral vector encoding sialyltransferase, an enzyme responsible for neural cell adhesion molecule polysialylation. In vitro, we found that ectopic expression of polysialylate promoted adult macaque Schwann cell migration and improved their integration among astrocytes in vitro without modifying their antigenic properties as either non-myelinating or pro-myelinating. In addition, forced expression of polysialylate in adult macaque Schwann cells decreased their adhesion with sister cells. To investigate the ability of adult macaque Schwann cells to integrate and migrate in vivo, focally induced demyelination was targeted to the spinal cord dorsal funiculus of nude mice, and both control and sialyltransferase expressing Schwann cells overexpressing green fluorescein protein were grafted remotely from the lesion site. Analysis of the spatio-temporal distribution of the grafted Schwann cells performed in toto and in situ, showed that in both groups, Schwann cells migrated towards the lesion site. However, migration of sialyltransferase expressing Schwann cells was more efficient than that of control Schwann cells, leading to their accelerated recruitment by the lesion. Moreover, ectopic expression of polysialylated neural cell adhesion molecule promoted adult macaque Schwann cell interaction with reactive astrocytes when exiting the graft, and their 'chain-like' migration along the dorsal midline. The accelerated migration of sialyltransferase expressing Schwann cells to the lesion site enhanced their ability to compete for myelin repair with endogenous cells, while control Schwann cells were unable to do so. Finally, remyelination by the exogenous sialyltransferase expressing Schwann cells restored the normal distribution of paranodal and nodal elements on the host axons. These greater performances of sialyltransferase expressing Schwann cell correlated with their sustained expression of polysialylated neural cell adhesion molecule at early times when migrating from the graft to the lesion, and its progressive downregulation at later times during remyelination. These results underline the potential therapeutic benefit to genetically modify Schwann cells to overcome their poor migration capacity and promote their repair potential in demyelinating disorders of the central nervous system.

Show MeSH
Related in: MedlinePlus