Homologous transplantation of neural stem cells to the injured spinal cord of mice

Roberto Pallini, Lucia Ricci Vitiani, Alessandra Bez, Patrizia Casalbore, Francesco Facchiano, Valeria Di Giorgi Gerevini, Maria Laura Falchetti, Eduardo Fernandez, Giulio Maira, Cesare Peschle, Eugenio Parati

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

OBJECTIVE: Murine neural stem cells (NSCs) were homografted onto the injured spinal cord (SC) to assess their potential to improve motor behavior, to differentiate as neurons, and to establish synapse-like contacts with the descending axonal paths of the host. In addition, we investigated whether transduced NSCs over-expressing vascular endothelial growth factor might exert any angiogenetic effect in the injured SC. METHODS: NSCs derived from mouse embryos were transduced to express either green fluorescent protein or vascular endothelial growth factor. The cells were engrafted in mice where an extended dorsal funiculotomy had been performed at the T8-T9 level. At intervals from 4 to 12 weeks after grafting, motor behavior was assessed using an open field locomotor scale and footprint analysis. At the same time points, the SC was studied by conventional histology, immunohistochemistry, and fluorescence microscopy. The interactions between the grafted NSCs and descending axonal paths were investigated using anterogradely transported fluorescent axonal tracers. RESULTS: By the 12-week time point mice engrafted with NSCs significantly improved both their locomotor score on open field test and their base of support on footprint analysis. Histological studies showed that green fluorescent protein-positive NSCs survived as long as 12 weeks after grafting, migrated from the grafting site with a tropism toward the lesion, and either remained undifferentiated or differentiated into the astrocytic phenotype without neuronal or oligodendrocytic differentiation. Interestingly, the NSC-derived astrocytes expressed vimentin, suggesting that these cells differentiated as immature astrocytes. The tips of severed descending axonal paths came adjacent to grafted NSCs without forming synapse-like structures. When genetically engineered to over-express vascular endothelial growth factor, the grafted NSCs significantly increased vessel density in the injured area. CONCLUSION: In the traumatically injured mice SC, NSC grafting improves motor recovery. Although differentiation of engrafted NSCs is restricted exclusively toward the astrocytic phenotype, the NSC-derived astrocytes show features that are typical of the early phase after SC injury when the glial scar is still permissive to regenerating axons. The immature phenotype of the NSC-derived astrocytes suggests that these cells might support neurite outgrowth by the host neurons. Thus, modifying the glial scar with NSCs might enhance axonal regeneration in the injured area. The use of genetically engineered NSCs that express trophic factors appears to be an attractive tool in SC transplantation research.

Original languageEnglish
Pages (from-to)1014-1024
Number of pages11
JournalNeurosurgery
Volume57
Issue number5
DOIs
Publication statusPublished - Nov 2005

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Neural Stem Cells
Homologous Transplantation
Spinal Cord
Astrocytes
Vascular Endothelial Growth Factor A
Green Fluorescent Proteins
Phenotype
Neuroglia
Synapses
Cicatrix
Neurons
Tropism
Vimentin
Spinal Cord Injuries
Fluorescence Microscopy
Axons

Keywords

  • Neural stem cells
  • Spinal cord injury
  • Transplantation

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

Pallini, R., Vitiani, L. R., Bez, A., Casalbore, P., Facchiano, F., Di Giorgi Gerevini, V., ... Parati, E. (2005). Homologous transplantation of neural stem cells to the injured spinal cord of mice. Neurosurgery, 57(5), 1014-1024. https://doi.org/10.1227/01.NEU.0000180058.58372.4c

Homologous transplantation of neural stem cells to the injured spinal cord of mice. / Pallini, Roberto; Vitiani, Lucia Ricci; Bez, Alessandra; Casalbore, Patrizia; Facchiano, Francesco; Di Giorgi Gerevini, Valeria; Falchetti, Maria Laura; Fernandez, Eduardo; Maira, Giulio; Peschle, Cesare; Parati, Eugenio.

In: Neurosurgery, Vol. 57, No. 5, 11.2005, p. 1014-1024.

Research output: Contribution to journalArticle

Pallini, R, Vitiani, LR, Bez, A, Casalbore, P, Facchiano, F, Di Giorgi Gerevini, V, Falchetti, ML, Fernandez, E, Maira, G, Peschle, C & Parati, E 2005, 'Homologous transplantation of neural stem cells to the injured spinal cord of mice', Neurosurgery, vol. 57, no. 5, pp. 1014-1024. https://doi.org/10.1227/01.NEU.0000180058.58372.4c
Pallini R, Vitiani LR, Bez A, Casalbore P, Facchiano F, Di Giorgi Gerevini V et al. Homologous transplantation of neural stem cells to the injured spinal cord of mice. Neurosurgery. 2005 Nov;57(5):1014-1024. https://doi.org/10.1227/01.NEU.0000180058.58372.4c
Pallini, Roberto ; Vitiani, Lucia Ricci ; Bez, Alessandra ; Casalbore, Patrizia ; Facchiano, Francesco ; Di Giorgi Gerevini, Valeria ; Falchetti, Maria Laura ; Fernandez, Eduardo ; Maira, Giulio ; Peschle, Cesare ; Parati, Eugenio. / Homologous transplantation of neural stem cells to the injured spinal cord of mice. In: Neurosurgery. 2005 ; Vol. 57, No. 5. pp. 1014-1024.
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AU - Casalbore, Patrizia

AU - Facchiano, Francesco

AU - Di Giorgi Gerevini, Valeria

AU - Falchetti, Maria Laura

AU - Fernandez, Eduardo

AU - Maira, Giulio

AU - Peschle, Cesare

AU - Parati, Eugenio

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N2 - OBJECTIVE: Murine neural stem cells (NSCs) were homografted onto the injured spinal cord (SC) to assess their potential to improve motor behavior, to differentiate as neurons, and to establish synapse-like contacts with the descending axonal paths of the host. In addition, we investigated whether transduced NSCs over-expressing vascular endothelial growth factor might exert any angiogenetic effect in the injured SC. METHODS: NSCs derived from mouse embryos were transduced to express either green fluorescent protein or vascular endothelial growth factor. The cells were engrafted in mice where an extended dorsal funiculotomy had been performed at the T8-T9 level. At intervals from 4 to 12 weeks after grafting, motor behavior was assessed using an open field locomotor scale and footprint analysis. At the same time points, the SC was studied by conventional histology, immunohistochemistry, and fluorescence microscopy. The interactions between the grafted NSCs and descending axonal paths were investigated using anterogradely transported fluorescent axonal tracers. RESULTS: By the 12-week time point mice engrafted with NSCs significantly improved both their locomotor score on open field test and their base of support on footprint analysis. Histological studies showed that green fluorescent protein-positive NSCs survived as long as 12 weeks after grafting, migrated from the grafting site with a tropism toward the lesion, and either remained undifferentiated or differentiated into the astrocytic phenotype without neuronal or oligodendrocytic differentiation. Interestingly, the NSC-derived astrocytes expressed vimentin, suggesting that these cells differentiated as immature astrocytes. The tips of severed descending axonal paths came adjacent to grafted NSCs without forming synapse-like structures. When genetically engineered to over-express vascular endothelial growth factor, the grafted NSCs significantly increased vessel density in the injured area. CONCLUSION: In the traumatically injured mice SC, NSC grafting improves motor recovery. Although differentiation of engrafted NSCs is restricted exclusively toward the astrocytic phenotype, the NSC-derived astrocytes show features that are typical of the early phase after SC injury when the glial scar is still permissive to regenerating axons. The immature phenotype of the NSC-derived astrocytes suggests that these cells might support neurite outgrowth by the host neurons. Thus, modifying the glial scar with NSCs might enhance axonal regeneration in the injured area. The use of genetically engineered NSCs that express trophic factors appears to be an attractive tool in SC transplantation research.

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