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.

Survival of Neural Stem Cell Grafts in the Lesioned Spinal Cord Is Enhanced by a Combination of Treadmill Locomotor Training via Insulin-Like Growth Factor-1 Signaling

“…Indeed, we found that the combination of TP and TMT led to the highest concentration of neurotrophic factors such as BDNF, NT-3, and, especially, GDNF at the epicenter region. Alternatively, the presence of more NSCs could exert more powerful modulatory effects on immune cells, leading to a greater amelioration of the secondary degenerative process (Cusimano et al, 2012). Enhanced survival should afford to provide a larger number of new neurons and oligodendrocytes derived from the NSCs to the lesioned spinal cord.…”

“…One of the hurdles that limits the efficacy of NSCs may be inadequate survival of NSC grafts (Yu et al, 2009;Li and Lepski, 2013). Previous studies have reported a rapid decline in the number of surviving NSCs grafted into the injured spinal cord (Okada et al, 2005;Cusimano et al, 2012).…”

“…One of these promising strategies is transplantation (TP) of neural stem/progenitor cells (NSCs; Karimi-Abdolrezaee and Eftekharpour, 2012;Ruff et al, 2012;Nakamura and Okano, 2013). Many studies have reported successful NSC TP with multiple therapeutic mechanisms in preclinical animal SCI models (Ben-Hur, 2010;Sahni and Kessler, 2010;Yasuda et al, 2011;Cusimano et al, 2012). However, the extent of reported neurological improvement is frequently modest (Ruff et al, 2012).…”

How stem cells speak with host immune cells in inflammatory brain diseases

“…4). These NPC-transplanted SCI mice show a reduction of proinflammatory M1-like macrophages at the injured site and develop much less severe secondary cord damage, compared with sham-operated controls (Cusimano et al, 2012) (Table 3).…”

“…Data in Table 1 are in part summarized in (Chamberlain et al, 2008;Hall et al, 2006;Martino and Pluchino 2006;Pluchino et al, 2009b;Rojewski et al, 2008;Uccelli et al, 2008;Yuan et al, 2011). (Cusimano et al, 2012;Jaderstad et al, 2010) aracrine IDO-kynurenine MSCs (h) T cells, DCs T cell apoptosis, inhibition of antigen presentation (Lanz et al, 2010;Matysiak et al, 2008Matysiak et al, , 2011Meisel et al, 2004;Plumas et al, 2005 Bonnamain et al, 2012;Chabannes et al, 2007;Moll et al, 2011) Paracrine VEGF NPCs Microglia/macrophages Inhibition of microglial activation, proliferation and phagocytosis (Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine LIF NPCs Th17 cells Inhibition of Th17 cell differentiation (Cao et al, 2011;Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine Galectins MSCs/NPCs T cells Inhibition of T cell proliferation (Gieseke et al, 2010;Sioud 2011;Yamane et al, 2010Yamane et al, , 2011 Endocrine/Paracrine TSG-6 MSCs Macrophages Inhibition of macrophage activation, proliferation and phagocytosis (Fisher-Shoval et al, 2012;Lee et al, 2009;Roddy et al, 2011) EVs miR transfer MSCs/NPCs Multiple Post-transcriptional regulation (Bruno et al, 2009;Chen et al, 2010;…”