title: Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord.
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.
authors.affiliation: Dept of Clinical Neurosciences, Cambridge Centre for Brain Repair and Cambridge Stem Cell Initiative, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
authors.forename: Melania
authors.initials: M
authors.lastname: Cusimano
authors.forename: Daniela
authors.initials: D
authors.lastname: Biziato
authors.forename: Elena
authors.initials: E
authors.lastname: Brambilla
authors.forename: Matteo
authors.initials: M
authors.lastname: Donegà
authors.forename: Clara
authors.initials: C
authors.lastname: Alfaro-Cervello
authors.forename: Silvia
authors.initials: S
authors.lastname: Snider
authors.forename: Giuliana
authors.initials: G
authors.lastname: Salani
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Pucci
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia-Verdugo
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.forename: Stefano
authors.initials: S
authors.lastname: Pluchino
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology*; D058953:Neural Stem Cells / Q000637:transplantation*; D010586:Phagocytes / Q000502:physiology*; D020127:Recovery of Function / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D016896:Treatment Outcome