Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R, Comi G, Constantin G, Martino GNeurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436:266-271

Neuroimmunology Unit-DIBIT, Vita-Salute University, San Raffaele Hospital, via Olgettina 58, 20132 Milan, Italy.
Nature (Impact Factor: 41.46). 08/2005; 436(7048):266-71. DOI: 10.1038/nature03889
Source: PubMed


In degenerative disorders of the central nervous system (CNS), transplantation of neural multipotent (stem) precursor cells (NPCs) is aimed at replacing damaged neural cells. Here we show that in CNS inflammation, NPCs are able to promote neuroprotection by maintaining undifferentiated features and exerting unexpected immune-like functions. In a mouse model of chronic CNS inflammation, systemically injected adult syngeneic NPCs use constitutively activated integrins and functional chemokine receptors to selectively enter the inflamed CNS. These undifferentiated cells survive repeated episodes of CNS inflammation by accumulating within perivascular areas where reactive astrocytes, inflamed endothelial cells and encephalitogenic T cells produce neurogenic and gliogenic regulators. In perivascular CNS areas, surviving adult NPCs induce apoptosis of blood-borne CNS-infiltrating encephalitogenic T cells, thus protecting against chronic neural tissue loss as well as disease-related disability. These results indicate that undifferentiated adult NPCs have relevant therapeutic potential in chronic inflammatory CNS disorders because they display immune-like functions that promote long-lasting neuroprotection.

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    • "MSCs possess great promise for clinical treatment of autoimmune diseases due to their extensive immunomodulatory properties. The FASL/FAS-mediated cell death pathway represents a typical mechanism of apoptotic signaling in many cell types (Hohlbaum et al. 2000; Pluchino et al. 2005; Zhang et al. 2008). Systemic infusion of MSCs can induce T-cell apoptosis via the FASL/FAS pathway, leading to upregulation of Tregs and immune tolerance (Akiyama et al. 2012). "
    Y Liu · C Chen · S Liu · D Liu · X Xu · X Chen · S Shi
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    ABSTRACT: Stem cells from exfoliated deciduous teeth (SHED) possess multipotent differentiation and immunomodulatory properties. They have been used for orofacial bone regeneration and autoimmune disease treatment. In this study, we show that acetylsalicylic acid (ASA) treatment is able to significantly improve SHED-mediated osteogenic differentiation and immunomodulation. Mechanistically, ASA treatment upregulates the telomerase reverse transcriptase (TERT)/Wnt/β-catenin cascade, leading to improvement of SHED-mediated bone regeneration, and also upregulates TERT/FASL signaling, leading to improvement of SHED-mediated T-cell apoptosis and ameliorating disease phenotypes in dextran sodium sulfate-induced colitis mice. These data indicate that ASA treatment is a practical approach to improving SHED-based cell therapy.
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    • "Fas-mediated cell death pathway represents typical apoptotic signaling in many cell types (Hohlbaum et al., 2000; Pluchino et al., 2005; Zhang et al., 2008). BMMSCs express FasL and can induce T-cell apoptosis via the FasL/Fas pathway, which may play a crucial role in BMMSC-based immunomodulation (Akiyama et al., 2012; Chen et al., 2014). "
    Y Liu · L Wang · S Liu · D Liu · C Chen · X Xu · X Chen · S Shi
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    ABSTRACT: Stem cells from human exfoliated deciduous teeth (SHED) are a unique postnatal stem cell population, possessing multipotent differentiation capacity and immunomodulatory properties. However, the mechanism by which SHED treat immune diseases is not fully understood. Here we show that systemic transplantation of SHED via the tail vein ameliorates ovariectomy (OVX)-induced osteopenia by reducing T-helper 1 (Th1) and T-helper 17 (Th17) cell numbers in the recipient OVX mice. Mechanistically, SHED transplantation induces activated T-cell apoptosis in OVX mice via Fas ligand (FasL)-mediated Fas pathway activation, leading to up-regulation of regulatory T-cells (Tregs) and down-regulation of Th1 and Th17 cells. This SHED-mediated immunomodulation rescues OVX-induced impairment of bone marrow mesenchymal stem cells (BMMSCs) and activation of osteoclastogenesis, resulting in increased bone mass. In summary, SHED-mediated T-cell apoptosis via a FasL/Fas pathway results in immune tolerance and ameliorates the osteopenia phenotype in OVX mice.
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    • "Indeed, NPCs grown in the presence of EGF and FGF2 achieved a stronger clinical effect when transplanted to EAE mice than NPCs grown with FGF2 alone. Multiple studies have shown that the main therapeutic effect of transplanted NPCs in EAE is via their immunomodulatory and neurotrophic properties, rather than participating directly in regeneration (Ben-Hur et al. 2007; Einstein et al. 2006; Pluchino et al. 2005). The improved therapeutic properties of FGF2-EGF NPCs may be partly related to their increased motility and glial preference, bringing them in close proximity to the site of inflammation and injury. "
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    ABSTRACT: Multiple sclerosis (MS) is a multifocal disease, and precursor cells need to migrate into the multiple lesions in order to exert their therapeutic effects. Therefore, cell migration is a crucial element in regenerative processes in MS, dictating the route of delivery, when cell transplantation is considered. We have previously shown that inflammation triggers migration of multi-potential neural precursor cells (NPCs) into white matter of experimental autoimmune encephalomyelitis (EAE) rodents, a widely used model of MS. Here we investigated the molecular basis of this attraction. NPCs were grown from E13 embryonic mouse brains and transplanted into the lateral cerebral ventricles of EAE mice. Transplanted NPC migration was directed by three tissue-derived chemokines. Stromal Cell-Derived Factor-1α, Monocyte Chemo-attractant Protein-1 and Hepatocyte Growth Factor were expressed in the EAE brain and specifically in microglia and astrocytes. Their cognate receptors, CXCR4, CCR2 or c-Met were constitutively expressed on NPCs. Selective blockage of CXCR4, CCR2 or c-Met partially inhibited NPC migration in EAE brains. Blocking all three receptors had an additive effect and resulted in profound inhibition of NPC migration, as compared to extensive migration of control NPCs. The inflammation-triggered NPC migration into white matter tracts was dependent on a motile NPC phenotype. Specifically, depriving NPCs from epidermal growth factor (EGF) prevented the induction of glial commitment and a motile phenotype (as indicated by an in vitro motility assay), hampering their response to neuroinflammation. In conclusion, signaling via three chemokine systems accounts for most of the inflammation-induced, tissue-derived attraction of transplanted NPCs into white matter tracts during EAE.
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