Dataset Information

Grafted human embryonic progenitors expressing neurogenin-2 stimulate axonal sprouting and improve motor recovery after severe spinal cord injury.

ABSTRACT:

Background

Spinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats.

Methods and principal findings

With the objective of translation to clinics we have chosen a paradigm of delayed grafting, i.e., one week after lesion, in a severe model of spinal cord compression in adult rats. hENPs were either naïve or engineered to express Neurogenin 2 (Ngn2). Moreover, we have compared integrating and non-integrating lentiviral vectors, since the latter present reduced risks of insertional mutagenesis. We show that transplantation of hENPs transduced to express Ngn2 fully restore weight support and improve functional motor recovery after severe spinal cord compression at thoracic level. This was correlated with partial restoration of serotonin innervations at lumbar level, and translocation of 5HT1A receptors to the plasma membrane of motoneurons. Since hENPs were not detectable 4 weeks after grafting, transitory expression of Ngn2 appears sufficient to achieve motor recovery and to permit axonal regeneration. Importantly, we also demonstrate that transplantation of naïve hENPs is detrimental to functional recovery.

Conclusions and significance

Transplantation and short-term survival of Ngn2-expressing hENPs restore weight support after SCI and partially restore serotonin fibers density and 5HT1A receptor pattern caudal to the lesion. Moreover, grafting of naïve-hENPs was found to worsen the outcome versus injured only animals, thus pointing to the possible detrimental effect of stem cell-based therapy per se in SCI. This is of major importance given the increasing number of clinical trials involving cell grafting developed for SCI patients.

SUBMITTER: Perrin FE

PROVIDER: S-EPMC3012721 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Publications

Grafted human embryonic progenitors expressing neurogenin-2 stimulate axonal sprouting and improve motor recovery after severe spinal cord injury.

Perrin Florence E FE Boniface Guillaume G Serguera Che C Lonjon Nicolas N Serre Angeline A Prieto Monica M Mallet Jacques J Privat Alain A

PloS one 20101230 12

<h4>Background</h4>Spinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats.<h4>Methods and principal findings</h4>With the objective of translation ...[more]

PMID: 21209909

Similar Datasets

Project description:Spinal cord contusion injury leads to severe loss of gray and white matter and subsequent deficit of motor and sensory functions below the lesion. In this study, we investigated whether application of murine clonal embryonic neuroectodermal stem cells can prevent the spinal cord secondary damage and induce functional recovery. Stem cells (NE-GFP-4C cell line) were grafted intraspinally or intravenously immediately or one week after thoracic spinal cord contusion injury. Control animals received cell culture medium or fibrin intraspinally one week after injury. Functional tests (Basso, Beattie, Bresnahan, CatWalk®) and detailed morphological analysis were performed to evaluate the effects of grafted cells. Stem cells applied either locally or intravenously induced significantly improved functional recovery compared with their controls. Morphologically, stem cell grafting prevented the formation of secondary injury and promoted sparing of the gray and white matters. The transplanted cells integrated into the host tissue and differentiated into neurons, astrocytes, and oligodendrocytes. In intraspinally grafted animals, the corticospinal tract axons regenerated along the ventral border of the cavity and have grown several millimeters, even beyond the caudal end of the lesion. The extent of regeneration and functional improvement was inversely related to the amounts of chondroitin sulphate and ephrin-B2 molecules around the cavity and to the microglial and astrocytic reactions in the injured segment early after injury. The grafts produced glial cell derived neurotrophic factor, macrophage inflammatory protein-1a, interleukin (IL)-6 and IL-10 in a paracrine fashion for at least one week. Treating the grafted cords with neutralizing antibodies against these four factors through the use of osmotic pumps nearly completely abolished the effect of the graft. The non-significant functional improvement after function blocking is likely because the stem cell derivatives settled in the injured cord. These data suggest that grafted neuroectodermal stem cells are able to prevent the secondary spinal cord damage and induce significant regeneration via multiple mechanisms.

Dataset Information

Grafted human embryonic progenitors expressing neurogenin-2 stimulate axonal sprouting and improve motor recovery after severe spinal cord injury.

Background

Methods and principal findings

Conclusions and significance

Publications

Grafted human embryonic progenitors expressing neurogenin-2 stimulate axonal sprouting and improve motor recovery after severe spinal cord injury.

Similar Datasets

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