Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord

Melania Cusimano, Daniela Biziato, Elena Brambilla, Matteo Doneg, Clara Alfaro-Cervello, Silvia Snider, Giuliana Salani, Ferdinando Pucci, Giancarlo Comi, Jose Manuel Garcia-Verdugo, Michele De Palma, Gianvito Martino, Stefano Pluchino

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

Transplanted neural stem/precursor cells possess peculiar therapeutic plasticity and can simultaneously instruct several therapeutic mechanisms in addition to cell replacement. Here, we interrogated the therapeutic plasticity of neural stem/precursor cells after their focal implantation in the severely contused spinal cord. We injected syngeneic neural stem/precursor cells at the proximal and distal ends of the contused mouse spinal cord and analysed locomotor functions and relevant secondary pathological events in the mice, cell fate of transplanted neural stem/precursor cells, and gene expression and inflammatory cell infiltration at the injured site. We used two different doses of neural stem/precursor cells and two treatment schedules, either subacute (7 days) or early chronic (21 days) neural stem/precursor cell transplantation after the induction of experimental thoracic severe spinal cord injury. Only the subacute transplant of neural stem/precursor cells enhanced the recovery of locomotor functions of mice with spinal cord injury. Transplanted neural stem/precursor cells survived undifferentiated at the level of the peri-lesion environment and established contacts with endogenous phagocytes via cellular-junctional coupling. This was associated with significant modulation of the expression levels of important inflammatory cell transcripts in vivo. Transplanted neural stem/precursor cells skewed the inflammatory cell infiltrate at the injured site by reducing the proportion of 'classically-activated' (M1-like) macrophages, while promoting the healing of the injured cord. We here identify a precise window of opportunity for the treatment of complex spinal cord injuries with therapeutically plastic somatic stem cells, and suggest that neural stem/precursor cells have the ability to re-programme the local inflammatory cell microenvironment from a 'hostile' to an 'instructive' role, thus facilitating the healing or regeneration past the lesion.

Original languageEnglish (US)
Pages (from-to)447-460
Number of pages14
JournalBrain
Volume135
Issue number2
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

Fingerprint

Neural Stem Cells
Phagocytes
Spinal Cord
Spinal Cord Injuries
Contusions
Cellular Microenvironment
Therapeutics
Adult Stem Cells
Recovery of Function
Stem Cell Transplantation
Plastics
Regeneration
Appointments and Schedules
Thorax
Macrophages
Transplants
Gene Expression

Keywords

  • cell transplantation
  • immune regulation
  • macrophages
  • neural stem cells
  • spinal cord injury
  • tissue healing

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Cusimano, M., Biziato, D., Brambilla, E., Doneg, M., Alfaro-Cervello, C., Snider, S., ... Pluchino, S. (2012). Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain, 135(2), 447-460. https://doi.org/10.1093/brain/awr339

Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. / Cusimano, Melania; Biziato, Daniela; Brambilla, Elena; Doneg, Matteo; Alfaro-Cervello, Clara; Snider, Silvia; Salani, Giuliana; Pucci, Ferdinando; Comi, Giancarlo; Garcia-Verdugo, Jose Manuel; De Palma, Michele; Martino, Gianvito; Pluchino, Stefano.

In: Brain, Vol. 135, No. 2, 01.01.2012, p. 447-460.

Research output: Contribution to journalArticle

Cusimano, M, Biziato, D, Brambilla, E, Doneg, M, Alfaro-Cervello, C, Snider, S, Salani, G, Pucci, F, Comi, G, Garcia-Verdugo, JM, De Palma, M, Martino, G & Pluchino, S 2012, 'Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord', Brain, vol. 135, no. 2, pp. 447-460. https://doi.org/10.1093/brain/awr339
Cusimano M, Biziato D, Brambilla E, Doneg M, Alfaro-Cervello C, Snider S et al. Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain. 2012 Jan 1;135(2):447-460. https://doi.org/10.1093/brain/awr339
Cusimano, Melania ; Biziato, Daniela ; Brambilla, Elena ; Doneg, Matteo ; Alfaro-Cervello, Clara ; Snider, Silvia ; Salani, Giuliana ; Pucci, Ferdinando ; Comi, Giancarlo ; Garcia-Verdugo, Jose Manuel ; De Palma, Michele ; Martino, Gianvito ; Pluchino, Stefano. / Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. In: Brain. 2012 ; Vol. 135, No. 2. pp. 447-460.
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